The critical role of osteopontin (OPN) in fibrotic diseases
骨连蛋白(OPN)在纤维性疾病中的关键作用

Osteopontin  骨桥蛋白
Secreted phosphoprotein 1
分泌性磷酸化蛋白 1
Fibrotic disease  纤维化疾病
Fibrosis  纤维化
Myofibroblast  肌成纤维细胞

Human fibrotic diseases constitute a significant human health problem, reflecting a global unmet medical need for therapeutic options [1]. Fibrosis is defined by the excessive deposition of extracellular matrix (ECM) produced by myofibroblasts that supersedes normal wound healing responses to injury and leads to fibrotic remodelling, organ destruction and ultimately organ failure [2,3]. Fibrosis can affect virtually every organ system, and it can be detected after tissue injury in the lungs, liver, kidney, heart and skin. However, the early stage of
人类纤维化疾病构成了一个重大的人类健康问题,反映了对治疗选择存在着全球未满足的医疗需求[1]。纤维化被定义为肌纤维母细胞产生的细胞外基质(ECM)的过度沉积,超过了伤害后正常的创伤愈合反应,导致纤维化重塑、器官破坏和最终器官衰竭[2,3]。纤维化可以影响几乎所有器官系统,可在肺、肝、肾、心和皮肤组织受伤后检测到。然而,早期的
fibrosis is challenging to diagnose since symptoms of organ dysfunction only occur when the organ is already moderately to severely compromised. Fibrosis is commonly associated with severe mortality due to incomplete knowledge of the pathogenesis of fibrotic processes, marked heterogeneity in disease aetiology and clinical presentations, the absence of appropriate and fully validated biomarkers, and, most importantly, a lack of available effective treatments [3]. Consequently, there is an urgent need for standardized diagnostic tools to detect early-stage fibrosis development and effective antifibrotic strategies grounded in well-established underlying mechanisms.
纤维化诊断具有挑战性,因为器官功能障碍的症状只有在器官已中度到重度受损的情况下才会出现。纤维化通常与严重的死亡率相关,这是由于对纤维化过程发病机制的知识不完整、疾病病因和临床表现的高度异质性、缺乏适当和完全验证的生物标志物,最重要的是缺乏有效的治疗手段[3]。因此,急需标准化的诊断工具来检测早期纤维化的发展,以及基于良好确立的潜在机制的有效抗纤维化策略。

https://doi.org/10.1016/j.cytogfr.2023.08.007
Received 18 July 2023; Received in revised form 22 August 2023; Accepted 22 August 2023
收到 2023 年 7 月 18 日; 收到修改后的版本 2023 年 8 月 22 日; 已接受 2023 年 8 月 22 日
Available online 23 August 2023
2023 年 8 月 23 日在线提供
1359-6101/© 2023 Elsevier Ltd. All rights reserved.
1359-6101/© 2023 Elsevier 有限公司保留所有权利。

Fig. 1. Genomic, transcriptional, and protein features of human OPN. The human Spp1 gene encodes the OPN protein and has seven exons. OPN transcripts have two starting points to generate secreted or/and intracellular forms. Alternative splicing of full-length Spp1 pre-mRNA results in five isoforms. All human OPN isoforms retain critical OPN domains and sites, such as the calcium-binding domain, heparin-binding domain, cleavage sites for thrombin and matrix metalloprotease, and domains with the amino acid sequences ELVTDFPTDLPAT, RGD and SVVYGLR. The receptor-interacting domains and the respective receptors for these domains are shown. Abbreviations: eex, extra exon.
图 1. 人类骨桥蛋白(OPN)的基因组、转录和蛋白质特征。人 Spp1 基因编码 OPN 蛋白,具有 7 个外显子。OPN 转录本有两个起始点,可产生分泌型和/或细胞内型。完整长度的 Spp1 前体 mRNA 经可选择性剪接产生 5 种等位体。所有人类 OPN 等位体均保留关键的 OPN 结构域和位点,如钙结合域、肝素结合域、血栓酶和基质金属蛋白酶的切割位点,以及含有 ELVTDFPTDLPAT、RGD 和 SVVYGLR 氨基酸序列的结构域。受体相互作用结构域及其相应的受体也显示在图中。缩写:eex,额外外显子。

Osteopontin (OPN), which is also referred to as bone sialoprotein 1 (BSP-1) and early T lymphocyte activation 1 (ETA-1), is a highly phosphorylated glycoprotein that is traditionally well recognized as an essential regulator of biomineralization and was first identified in bone tissue in 1986 [4,5]. The prefix “osteo-” is derived from “bone” and the suffix “-pontin” means “bridge”, indicating the role of OPN as a bridging protein within the bone ECM. Indeed, OPN is expressed by a wide variety of cell types. Accumulating evidence has demonstrated that OPN can act as an ECM component, a soluble cytokine or an intracytoplasmic molecule involved in mineralization, inflammation, immune response, and wound healing associated with a variety of pathophysiological processes that play crucial roles in tissue remodelling [6,7].
骨桥蛋白(OPN)，也称为骨硅蛋白 1(BSP-1)和早期 T 淋巴细胞激活 1(ETA-1)，是一种高度磷酸化的糖蛋白，传统上被认为是生物矿化的关键调节因子，于 1986 年首次在骨组织中发现[4,5]。"骨骼"前缀来自"骨骼"，"桥"后缀意味着 OPN 在骨基质中起到桥梁作用。事实上,OPN 由多种细胞类型表达。越来越多的证据表明,OPN 可作为细胞外基质成分、可溶性细胞因子或参与矿化、炎症、免疫反应和创伤愈合的胞内分子,在组织重塑的各种病理生理过程中起关键作用[6,7]。

Over the past decades, studies have indicated close links between OPN and fibrotic diseases. Notably, relatively high local levels of OPN were found in fibrotic lungs, liver, kidney, heart and other tissues, indicating its potential involvement in the development of fibrosis. This review summarizes the current understanding of how OPN affects the development and severity of fibrosis in different organs and tissues. Additional discussions focus on its potential as a biomarker and novel therapeutic target for fibrotic diseases.
过去几十年的研究表明,OPN 与纤维化疾病存在密切联系。值得注意的是,纤维化肺、肝、肾、心等组织中发现 OPN 局部水平相对较高,表明它可能参与了纤维化的发展。本文综述了 OPN 如何影响不同器官和组织纤维化的发展及其严重程度的现有认知。此外,还讨论了它作为生物标志物和治疗纤维化疾病的新靶点的潜力。

OPN, which is a negatively charged and highly acidic protein, belongs to the small integrin-binding ligand N -linked glycoprotein
OPN 是一种带有负电荷且高度酸性的蛋白质,属于小型整合素结合配体 N-连接糖蛋白
(SIBLING) protein family based on biochemical and genetic features rather than standard functions [8]. The functions of OPN are based on its gene polymorphisms, posttranslational modifications (PTMs) (phosphorylation, O-linked glycosylation, sialylation, and tyrosine sulfation), splice variants, binding domains and cleavage.
基于生化和遗传特征而非标准功能的(同胞)蛋白质家族[8]。OPN 的功能基于其基因多态性、翻译后修饰(磷酸化、O-连接糖基化、唾液酸化和酪氨酸磺酸化)、剪接变体、结合域和切割。

In humans, OPN is encoded by the secreted phosphoprotein 1 (Spp1) gene on chromosome 4 near the centromere (4q22.1), which spans 7.8 kilobases and is composed of seven exons and six introns [9]. In contrast, the mouse Spp1 gene is located on chromosome 5 and has an approximately 6 kilobases coding region, including eight exons [10]. Human Spp1 is $\sim 84\mathrm{\%}$$\sim 84\mathrm{\%}$∼84%\sim 84 \% homologous to the mouse Spp1 gene [9,11]. In the human Spp1 gene, the first exon is untranslated, and exons $2-7$$2-7$2-72-7 contain the coding sequences [6]: exon 2 contains part of the 5 ’ UTR, the signal peptide, and the first two amino acids (aa) of the mature protein; exon 3 contains diverse consensus sequences for serine phosphorylation and the EESS consensus sequence for casein kinase II; exon 4 contains the target sequence for transglutaminase, and can bind to the ECM via a transglutaminase linkage to facilitate cellular attachment and tissue calcification; exon 5 generally contains the second phosphorylation EESS consensus site for casein kinase II; and exons 6 and 7 typically encode more than $80\mathrm{\%}$$80\mathrm{\%}$80%80 \% of each protein and contain three integrin domains [9, 12] (Fig. 1). Single nucleotide polymorphisms of the Spp1 gene in
在人类中,OPN 由位于第 4 号染色体近着丝粒的分泌磷蛋白 1(Spp1)基因编码(4q22.1),该基因跨越 7.8 千碱基,由七个外显子和六个内含子组成[9]。相比之下,小鼠 Spp1 基因位于第 5 号染色体,编码区约为 6 千碱基,包括八个外显子[10]。人类 Spp1 与小鼠 Spp1 基因高度同源[9,11]。在人类 Spp1 基因中,第一个外显子未被翻译,外显子 $2-7$$2-7$2-72-7 包含编码序列[6]:外显子 2 包含部分 5'非翻译区、信号肽和成熟蛋白的前两个氨基酸(aa);外显子 3 包含多个丝氨酸磷酸化共识序列以及酪蛋白激酶 II 的 EESS 共识序列;外显子 4 包含转谷氨酰胺酶的靶序列,可通过转谷氨酰胺酶的连接与细胞外基质结合,以促进细胞粘附和组织钙化;外显子 5 通常包含酪蛋白激酶 II 的第二个磷酸化 EESS 共识位点;而外显子 6 和 7 通常编码每个蛋白质的 $80\mathrm{\%}$$80\mathrm{\%}$80%80 \% 以上,并包含三个整合素结构域[9,12](图 1)。Spp1 基因的单核苷酸多态性在
humans and mice influence OPN protein expression, and the human Spp1 gene participates in cancer and autoimmune disease development, progression, and prognosis [6,9,13].
人类和小鼠影响 OPN 蛋白表达,人类 Spp1 基因参与肿瘤和自身免疫疾病的发展、进展和预后。[6,9,13]

The human OPN protein consists of approximately 314 aa, and its apparent molecular weight ranges from 40 to 80 kDa due to alternative splicing and PTMs [14]. Similarly, the full-length mouse OPN protein consists of 294 aa and exhibits a comparable molecular weight range of $40-80\mathrm{kDa}$$40-80\mathrm{kDa}$40-80kDa40-80 \mathrm{kDa}, as shown by SDS-PAGE [10]. Although the OPN peptide sequences in humans and mice share only $63\mathrm{\%}$$63\mathrm{\%}$63%63 \% homology, several structures and motifs in OPN are highly conserved across species [15]. Additionally, OPN lacks a well-defined tertiary structure and often lacks a secondary structure, exhibiting eight $\alpha$$\alpha$alpha\alpha-helices and six $\beta$$\beta$beta\beta-sheets [16, 17].
人类 OPN 蛋白约由 314 个氨基酸组成,由于替代剪接和翻译后修饰,其表观分子量在 40 至 80kDa 之间[14]。同样,全长小鼠 OPN 蛋白由 294 个氨基酸组成,其分子量范围也在 $40-80\mathrm{kDa}$$40-80\mathrm{kDa}$40-80kDa40-80 \mathrm{kDa} 之间,如 SDS-PAGE 所示[10]。尽管人类和小鼠 OPN 肽序列的同源性仅为 $63\mathrm{\%}$$63\mathrm{\%}$63%63 \% ,但 OPN 中的几种结构和结构域在物种之间高度保守[15]。此外,OPN 缺乏明确的三级结构,通常也缺乏二级结构,呈现八个 $\alpha$$\alpha$alpha\alpha -螺旋和六个 $\beta$$\beta$beta\beta -折叠[16,17]。

Depending on differences in alternative splicing and the site of initiation of the Spp1 pre-mRNA, OPN has different isoforms. Alternative splicing of full-length Spp1 pre-mRNA results in 5 isoforms, which are mainly studied as human OPN: OPN-a (the full-length isoform; 314 aa), OPN-b (lacking exon 5; 300 aa), OPN-c (lacking exon 4; 287 aa), OPN-4 (lacking exons 4 and 5; 273 aa), and OPN-5 (with an extra exon involved in the retention of a portion of intron 3 and a different start codon; lacking exon 2 and exon 3; 327 aa) [9,11] (Fig. 1). OPN-c is not able to crosslink and form polymeric complexes because of a lack of exon 4 [12]. Intracellular OPN (i-OPN) is another truncated version lacking the signal peptide (aa 1-16) transcription due to the initiation of translation from a downstream noncanonical start codon that prevents OPN secretion [18] (Fig. 1). Mouse and human OPN were identified in the cytoplasm and nucleus of cells. Different OPN isoforms have different physiological and pathological functions. However, most data on fibrotic diseases refer to total OPN, including the different OPN isoforms, and reports describing the expression and roles of each OPN isoform are scarce.
根据 Spp1 前体 mRNA 的可选择性剪接和起始位点的不同,OPN 具有不同的等位基因。Spp1 全长前体 mRNA 的可选择性剪接产生 5 种等位基因,主要研究作为人 OPN:OPN-a(全长等位基因;314 氨基酸)、OPN-b(缺失第 5 外显子;300 氨基酸)、OPN-c(缺失第 4 外显子;287 氨基酸)、OPN-4(缺失第 4 和第 5 外显子;273 氨基酸)以及 OPN-5(涉及保留部分第 3 内含子和不同起始密码子的额外外显子;缺失第 2 和第 3 外显子;327 氨基酸)[9,11](图 1)。由于缺失第 4 外显子,OPN-c 无法交联并形成聚合物[12]。不含信号肽(1-16 氨基酸)的截短版本 i-OPN 是另一种由于从下游非经典起始密码子启动翻译而无法分泌的 OPN[18](图 1)。小鼠和人类 OPN 在细胞的细胞质和核中都有发现。不同的 OPN 等位基因具有不同的生理和病理功能。然而,大多数关于纤维化疾病的数据涉及总的 OPN,包括不同的 OPN 等位基因,而描述每种 OPN 等位基因的表达和作用的报告很少。

OPN proteins exert physiological and pathological effects through the binding of their domains to the corresponding ligands. Integrins and CD44 receptors are among the known binding partners of OPN. There are three integrin domains in human OPN near the N -terminus: the nonconserved ELVTDFPTDLPAT (aa 131-143) domain acts as ligands for $\alpha 4\beta 1$$\alpha 4\beta 1$alpha4beta1\alpha 4 \beta 1 integrins [19]; the conserved arginine-glycine-aspartic acid (RGD) domain (aa 159-161) mainly engages ${\alpha }_v\beta 1,{\alpha }_v\beta 3,{\alpha }_v\beta 5$${\alpha }_v\beta 1,{\alpha }_v\beta 3,{\alpha }_v\beta 5$alpha_(v)beta1,alpha_(v)beta3,alpha_(v)beta5\alpha_{v} \beta 1, \alpha_{v} \beta 3, \alpha_{v} \beta 5, ${\alpha }_v\beta 6$${\alpha }_v\beta 6$alpha_(v)beta6\alpha_{v} \beta 6, ${\alpha }_{\mathrm{v}}\beta 8,\alpha 5\beta 1$${\alpha }_{\mathrm{v}}\beta 8,\alpha 5\beta 1$alpha_(v)beta8,alpha5beta1\alpha_{\mathrm{v}} \beta 8, \alpha 5 \beta 1 and $\alpha 8\beta 1$$\alpha 8\beta 1$alpha8beta1\alpha 8 \beta 1 integrins [20]; and thrombin cleaves OPN at a conserved site $\left({}^{168}{\mathrm{RS}}^{169}\right)$$\left({}^{168}{\mathrm{RS}}^{169}\right)$(^(168)RS^(169))\left({ }^{168} \mathrm{RS}^{169}\right) and exposes a cryptic SVVYGLR (aa 162-168; SLAYGLR in mouse) domain that allows for the interaction between OPN and integrin receptors $\alpha 4\beta 1,\alpha 4\beta 7$$\alpha 4\beta 1,\alpha 4\beta 7$alpha4beta1,alpha4beta7\alpha 4 \beta 1, \alpha 4 \beta 7 and $\alpha 9\beta 1$$\alpha 9\beta 1$alpha9beta1\alpha 9 \beta 1 [21-23]. In addition, matrix metalloproteinase (MMP)-3 and MMP-7 cleave OPN at the site $\left({}^{166}{\mathrm{GL}}^{167}\right)$$\left({}^{166}{\mathrm{GL}}^{167}\right)$(^(166)GL^(167))\left({ }^{166} \mathrm{GL}^{167}\right) of the SVVYGLR domain, and the cleaved product is recognized by $\alpha 4\beta 1$$\alpha 4\beta 1$alpha4beta1\alpha 4 \beta 1 integrin [24]. There is one calcium-binding domain (aa $216-228$$216-228$216-228216-228 ) and two heparin-binding domains (aa 165-174 and aa 298-305) near the C-terminus that can be recognized by the v3, v6, and v7 splice variants of CD44 [11,25] (Fig. 1). Interestingly, the thrombin and MMP-3/7 cleavage domains are located close to one heparin-binding domain (aa 165-174). Therefore, heparin binding to the domain may block access to thrombin and MMP-3/7 and maintain the full-length form of OPN.
OPN 蛋白通过与相应配体结合其结构域而产生生理和病理效应。整合素和 CD44 受体是 OPN 已知的结合伙伴。人类 OPN 靠近 N 端有三个整合素结合域:不保守的 ELVTDFPTDLPAT(氨基酸 131-143)域作为 $\alpha 4\beta 1$$\alpha 4\beta 1$alpha4beta1\alpha 4 \beta 1 整合素的配体;保守的精氨酸-甘氨酸-天冬氨酸(RGD)域(氨基酸 159-161)主要与 ${\alpha }_v\beta 1,{\alpha }_v\beta 3,{\alpha }_v\beta 5$${\alpha }_v\beta 1,{\alpha }_v\beta 3,{\alpha }_v\beta 5$alpha_(v)beta1,alpha_(v)beta3,alpha_(v)beta5\alpha_{v} \beta 1, \alpha_{v} \beta 3, \alpha_{v} \beta 5 、 ${\alpha }_v\beta 6$${\alpha }_v\beta 6$alpha_(v)beta6\alpha_{v} \beta 6 、 ${\alpha }_{\mathrm{v}}\beta 8,\alpha 5\beta 1$${\alpha }_{\mathrm{v}}\beta 8,\alpha 5\beta 1$alpha_(v)beta8,alpha5beta1\alpha_{\mathrm{v}} \beta 8, \alpha 5 \beta 1 和 $\alpha 8\beta 1$$\alpha 8\beta 1$alpha8beta1\alpha 8 \beta 1 整合素结合;凝血酶在一个保守位点 $\left({}^{168}{\mathrm{RS}}^{169}\right)$$\left({}^{168}{\mathrm{RS}}^{169}\right)$(^(168)RS^(169))\left({ }^{168} \mathrm{RS}^{169}\right) 切割 OPN,暴露出一个隐藏的 SVVYGLR(氨基酸 162-168;小鼠中为 SLAYGLR)域,允许 OPN 与整合素受体 $\alpha 4\beta 1,\alpha 4\beta 7$$\alpha 4\beta 1,\alpha 4\beta 7$alpha4beta1,alpha4beta7\alpha 4 \beta 1, \alpha 4 \beta 7 和 $\alpha 9\beta 1$$\alpha 9\beta 1$alpha9beta1\alpha 9 \beta 1 相互作用。另外,基质金属蛋白酶(MMP)-3 和 MMP-7 在 SVVYGLR 域的位点 $\left({}^{166}{\mathrm{GL}}^{167}\right)$$\left({}^{166}{\mathrm{GL}}^{167}\right)$(^(166)GL^(167))\left({ }^{166} \mathrm{GL}^{167}\right) 切割 OPN,切割产物被 $\alpha 4\beta 1$$\alpha 4\beta 1$alpha4beta1\alpha 4 \beta 1 整合素识别。靠近 C 端有一个结合钙的域(氨基酸 $216-228$$216-228$216-228216-228 )和两个结合肝素的域(氨基酸 165-174 和 298-305),可被 CD44 的 v3、v6 和 v7 剪接体识别。有趣的是,凝血酶和 MMP-3/7 的切割位点靠近一个肝素结合域(氨基酸 165-174)。因此,肝素与该结合域的结合可能阻碍凝血酶和 MMP-3/7 的作用,维持 OPN 的完整形式。

OPN is produced by a variety of cell types, including B cells, T cells, natural killer (NK) cells, NKT lymphocytes, macrophages, neutrophils, dendritic cells (DCs), bone cells (osteoblasts and osteocytes), epithelial cells, and neurons, and OPN has been detected in human lungs, liver, bone, joint, brain and adipose tissue. Most Spp1 encodes signal peptides that mediate cellular secretion and accumulation in blood, urine, bile, and milk $[6,7]$$[6,7]$[6,7][6,7]. The many distribution sites of OPN reflect the involvement of OPN in multiple physiological processes. The binding of OPN to
OPN 由各种细胞类型产生,包括 B 细胞、T 细胞、自然杀伤(NK)细胞、NKT 淋巴细胞、巨噬细胞、中性粒细胞、树突状细胞(DC)、骨细胞(成骨细胞和骨细胞)、上皮细胞和神经元,OPN 已在人类肺、肝、骨骼、关节、大脑和脂肪组织中检测到。大多数 Spp1 编码信号肽,介导细胞分泌并在血液、尿液、胆汁和乳汁中积累。OPN 分布广泛反映了其在多种生理过程中的参与。OPN 与
integrins or CD44 participates in mineralization, the immune response and wound healing by activating signalling pathways that regulate cell proliferation, adhesion and migration.
整合素或 CD44 参与矿化、免疫反应和创伤愈合,通过激活调节细胞增殖、黏附和迁移的信号通路来实现。

OPN enhances the adhesion of osteoblasts and osteoclasts to the bone matrix and stimulates osteoclast activity through interactions with the OPN receptors $\alpha v\beta 3$$\alpha v\beta 3$alpha v beta3\alpha v \beta 3 and CD44, resulting in bone resorption [26-28]. Additionally, OPN is secreted by osseous cells and regulates the functions of monocyte-derived cells, including phagocytic macrophages, which play a role in the resorption process [29]. Furthermore, in studies involving OPN-knockout ( ${\mathrm{OPN}}^{-/}$${\mathrm{OPN}}^{-/}$OPN^(-//)\mathrm{OPN}^{-/}) mice, enhanced mineralization has been observed in bone and calcified cartilage [30], atherosclerosis [31] and kidney tubules [32]. That is, OPN suppresses hydroxyapatite accumulation and crystal growth during mineralization.
骨鞘蛋白(OPN)通过与 OPN 受体 $\alpha v\beta 3$$\alpha v\beta 3$alpha v beta3\alpha v \beta 3 和 CD44 的相互作用,增强成骨细胞和破骨细胞对骨基质的粘附性,并刺激破骨细胞活性,导致骨吸收[26-28]。此外,OPN 也由骨组织细胞分泌,调节单核细胞衍生细胞(包括吞噬性巨噬细胞)的功能,这些细胞在骨吸收过程中起作用[29]。此外,在涉及 OPN 敲除( ${\mathrm{OPN}}^{-/}$${\mathrm{OPN}}^{-/}$OPN^(-//)\mathrm{OPN}^{-/} )小鼠的研究中,观察到骨骼和钙化软骨[30]、动脉粥样硬化[31]和肾小管[32]中矿化的增强。也就是说,OPN 抑制羟基磷灰石的积累和结晶生长,从而抑制矿化。

OPN also regulates immunity under physiological conditions. Its regulatory role is particularly evident in the development of proinflammatory T helper (Th) type-1 and Th17 cells. Specifically, OPN induces the hypomethylation of interferon- $\gamma$$\gamma$gamma\gamma (IFN- $\gamma$$\gamma$gamma\gamma ) and interleukin (IL)17a, enhancing the differentiation of Th1 and Th17 cells by interacting with CD44 in Th cells. Furthermore, OPN promotes the Th1-mediated inflammatory response and increases IL-17 production by Th17 cells [33]. In DCs, i-OPN inhibits IL-27 expression while enhancing the response of Th17 cells [6]. Additionally, OPN mediates the chemotactic properties of macrophages, DCs, mast cells, and T cells, stimulates antibody production by B cells, regulates nitric oxide production, and facilitates efficient type-1 immune responses [26,33-35]. Numerous studies have explored the relationship between OPN and the immune response, and for further in-depth discussions on this topic, we recommend referring to several outstanding review articles $[6,10,36]$$[6,10,36]$[6,10,36][6,10,36].
骨桥蛋白(OPN)在生理条件下也调节免疫。其调节作用尤其表现在促炎性 T 辅助(Th)1 型和 Th17 细胞的发育中。具体而言,OPN 诱导干扰素-γ(IFN-γ)和白细胞介素(IL)17a 的去甲基化,通过与 Th 细胞上的 CD44 相互作用,增强 Th1 和 Th17 细胞的分化。此外,OPN 还促进 Th1 介导的炎症反应,并增加 Th17 细胞分泌 IL-17[33]。在树突状细胞(DCs)中,i-OPN 抑制 IL-27 的表达,同时增强 Th17 细胞的反应[6]。另外,OPN 介导巨噬细胞、DCs、肥大细胞和 T 细胞的趋化性,刺激 B 细胞产生抗体,调节一氧化氮的产生,并促进有效的 1 型免疫反应[26,33-35]。许多研究已探讨了 OPN 与免疫反应之间的关系,对这一主题的深入讨论,我们建议参考几篇优秀的综述文章[code2]。

Another significant physiological function of OPN is its involvement in the promotion of wound healing, which has garnered considerable attention. Studies have demonstrated that OPN expression is increased during wound healing compared to that in healthy skin. In a study by Liaw and colleagues, ${\mathrm{OPN}}^{-/-}$${\mathrm{OPN}}^{-/-}$OPN^(-//-)\mathrm{OPN}^{-/-}mice exhibited healed wounds with a less organized matrix characterized by reduced collagen fibres, less organized arrangement, and decreased fibril diameters [37]. Ken-ichi’s study showed that cuts in the corneas of ${\mathrm{OPN}}^{-/-}$${\mathrm{OPN}}^{-/-}$OPN^(-//-)\mathrm{OPN}^{-/-}mice experienced delayed healing, a reduced presence of fibroblasts and reduced expression of transforming growth factor- $\beta 1$$\beta 1$beta1\beta 1 (TGF- $\beta 1$$\beta 1$beta1\beta 1 ), resulting in an increased incidence of corneal perforation [38]. OPN facilitates the mobilization of bone marrow-derived stem cells into wounds by interacting with CD44, thereby promoting their transdifferentiation into multiple skin cell types that contribute to wound repair [39]. Additionally, OPN plays a role in the recruitment, regulation and differentiation of (myo)fibroblasts, facilitating the proper deposition of ECM components and collagen during wound healing [40]. Notably, while OPN is essential for proper wound healing, prolonged production or excessive levels of OPN can lead to fibrosis and excess scar formation, which is discussed in the subsequent section.
另一个 OPN 的重要生理功能是在伤口愈合过程中的参与,这引起了人们的广泛关注。研究表明,与健康皮肤相比,OPN 在伤口愈合过程中的表达水平会增加。在 Liaw 和同事的研究中, ${\mathrm{OPN}}^{-/-}$${\mathrm{OPN}}^{-/-}$OPN^(-//-)\mathrm{OPN}^{-/-} 小鼠的愈合伤口表现出较不规整的基质,特征为胶原纤维减少、排列无序以及纤维直径降低[37]。Ken-ichi 的研究显示, ${\mathrm{OPN}}^{-/-}$${\mathrm{OPN}}^{-/-}$OPN^(-//-)\mathrm{OPN}^{-/-} 小鼠角膜切口愈合延迟,成纤维细胞的数量减少,以及转化生长因子- $\beta 1$$\beta 1$beta1\beta 1 (TGF- $\beta 1$$\beta 1$beta1\beta 1 )表达降低,导致角膜穿孔发生率增加[38]。OPN 通过与 CD44 相互作用,促进骨髓源性干细胞向伤口的转移,从而推动其向多种皮肤细胞类型的跨分化,对伤口修复有贡献[39]。此外,OPN 在(肌)成纤维细胞的 recruitment、调控和分化中发挥作用,促进细胞外基质成分和胶原的适当沉积,从而推进伤口愈合[40]。值得注意的是,尽管 OPN 对适当的伤口愈合至关重要,但其持续过度产生或过高水平会导致纤维化和瘢痕形成过度,这在后续部分中有所讨论。

Moreover, recent studies on OPN have provided strong evidence for its essential roles in infant intestinal proliferation and maturation, brain myelination, neurodevelopment, and immune development when present in breast milk [41-43]. These findings highlight the biotransformational value of OPN in breast milk.
此外,近期关于 OPN 的研究为其在婴儿肠道增殖和成熟、脑髓鞘化、神经发育以及免疫发育中的关键作用提供了有力证据[41-43]。这些发现突出了 OPN 在母乳中的生物转化价值。

The association of OPN with the progression of fibrotic disease has recently attracted attention, resulting in accumulating evidence. In general, high levels of OPN correlate with a more severe phenotype and a worse prognosis for fibrotic diseases. In this section, we review studies on pulmonary fibrosis and other fibrotic diseases, and there is a plethora of literature related to OPN.
骨利蛋白(OPN)与纤维性疾病进展的关联近来引起了关注,并产生了大量的证据。通常,OPN 水平较高与更严重的表型和纤维性疾病预后较差相关。在本节中,我们回顾了肺纤维化和其他纤维性疾病的研究,并且与 OPN 相关的文献资料丰富。

Pulmonary fibrosis is a chronic, heterogeneous, fatal respiratory
肺纤维化是一种慢性、异质性、致命的呼吸系统疾病

Fig. 2. BLM-induced pulmonary fibrosis in C57BL/6 J mice. Tissue sections of mouse lungs. H&E, Masson, and immunohistochemically stained (OPN) sections were observed under a light microscope (Obj $50\times$$50\times$50 xx50 \times, Bar $=50\mu \mathrm{m}$$=50\mu \mathrm{m}$=50 mum=50 \mu \mathrm{~m} ). Compared with those in the control group, high levels of OPN were found locally in the fibrotic lungs of BLM-induced mice. Abbreviations: IHC, Immunohistochemistry.
图 2. BLM 诱导的 C57BL/6J 小鼠肺纤维化。小鼠肺组织切片。在光学显微镜下观察 H&E 染色、马松染色和免疫组织化学染色(OPN)切片(目镜 $50\times$$50\times$50 xx50 \times ，标尺 $=50\mu \mathrm{m}$$=50\mu \mathrm{m}$=50 mum=50 \mu \mathrm{~m} )。与对照组相比,BLM 诱导的小鼠纤维化肺局部检测到高水平的 OPN。缩写:IHC,免疫组织化学。
disease with different causes. Clinically, pulmonary fibrosis is commonly divided into idiopathic pulmonary fibrosis (IPF) with unknown aetiology and secondary pulmonary fibrosis with known aetiology, such as connective tissue disease (CTD), drugs, dust, and infection. The pathogenesis of pulmonary fibrosis includes but is not limited to three main contributing factors [44-48]: (1) repetitive epithelial injury with progenitor cell dysfunction; (2) persistent inflammatory and immune responses by immune cells due to long-term injury; and (3) the differentiation and activation of (myo)fibroblasts, which are the central producers of the ECM, resulting in irreversible changes to lung morphology leading to impaired pulmonary function and high mortality rates.
肺纤维化是具有不同病因的疾病。从临床上来看,肺纤维化通常分为特发性肺纤维化(IPF)和继发性肺纤维化两种,其中特发性肺纤维化病因不明,继发性肺纤维化则有明确病因,如胶原血管病、药物、粉尘和感染等。肺纤维化的发病机制主要包括但不限于三大因素:1)上皮细胞反复受损、干细胞功能障碍;2)长期受损致使免疫细胞持续炎症和免疫反应;3)成纤维细胞及肌成纤维细胞的分化和激活,这些细胞是细胞外基质的主要产生者,导致肺形态学发生不可逆的变化,从而引起肺功能受损,死亡率较高。

Under physiological conditions, OPN expression in adult lung tissue is primarily limited to macrophages, bronchioles, fibroblasts, and endothelial cells and occurs at low levels. In an inflammatory environment in the lung, cytokines such as monocyte colony-stimulating factor (MCSF), IL-6, IL-1 $\beta$$\beta$beta\beta, and IL-33 have been shown to upregulate OPN expression [49-52]. During lung fibrogenesis, the airway epithelium, alveolar macrophages, and activated fibroblasts are major sources of OPN production [49,53-55]. Additionally, there is a notable increase in OPN expression in lung tissue and bronchoalveolar lavage fluid (BALF), and this increase is correlated with the severity of fibrosis [56-58] (Fig. 2). Inhibiting OPN reduces fibrosis severity in animal models of pulmonary fibrosis [59-63]. Previous studies have indicated that the mechanistic association between OPN and pulmonary fibrosis primarily involves progenitor cell repair, immunoregulation, and the facilitation of myofibroblast differentiation and activation.
在生理条件下,成人肺组织中 OPN 的表达主要局限于巨噬细胞、细支气管、成纤维细胞和内皮细胞,且表达水平较低。在肺部炎症环境中,单核细胞集落刺激因子(MCSF)、IL-6、IL-1 和 IL-33 等细胞因子已被证明可上调 OPN 的表达[49-52]。在肺纤维化过程中,气道上皮细胞、肺泡巨噬细胞和活化的成纤维细胞是 OPN 产生的主要来源[49、53-55]。此外,肺组织和支气管肺泡灌洗液(BALF)中 OPN 的表达明显增加,并且这种增加与纤维化的严重程度相关[56-58](图 2)。抑制 OPN 可减轻动物肺纤维化模型中的纤维化严重程度[59-63]。既往研究表明,OPN 与肺纤维化之间的机制联系主要涉及到祖细胞修复、免疫调节以及促进肌成纤维细胞分化和激活。

Club cells are considered progenitor cells in human terminal bronchioles and respiratory bronchioles. These cells play a role in repairing the regional epithelium in response to lung damage and are present in the distal lung in IPF, suggesting their association with lung fibrosis [64-66]. A recent study by Kumar and colleagues demonstrated that
俱乐部细胞被认为是人类末端细支气管和呼吸性细支气管的祖细胞。这些细胞在肺损伤后参与修复区域上皮,并存在于特发性肺纤维化患者的远端肺部,这表明它们与肺纤维化有关。Kumar 及同事最近的一项研究表明,
specific depletion of protein disulfide isomerase A3 (PDIA3) in club cells reduced the production of OPN/Spp1 in experimental fibrosis and subsequent improvements in fibrosis [63]. This finding suggests that OPN/Spp1 interacts with and is influenced by club cell PDIA3, which may be involved in progenitor cell repair disorders following repeated epithelial cell injury in the context of lung fibrosis [63].
特异性消耗蛋白二硫化物异构酶 A3(PDIA3)减少了实验性纤维化中 OPN/Spp1 的产生,并改善了纤维化[63]。这一发现表明,OPN/Spp1 与俱乐部细胞 PDIA3 相互作用并受其影响,可能参与了肺纤维化背景下重复上皮细胞损伤后的祖细胞修复紊乱[63]。

Several studies have revealed the link between OPN and immune cells in lung fibrosis. First, OPN plays a role in bleomycin (BLM)-induced lung inflammation and fibrosis by influencing the pathogenic IL-17/ protective IFN- $\gamma$$\gamma$gamma\gamma T-cell ratio [67]. Second, pathogenic memory Th2 cells produce amphiregulin during airway fibrosis in asthma; amphiregulin-mediated signalling directly reprograms eosinophils to an inflammatory state and enhances the production of OPN, which directs fibrotic responses in eosinophilic airway inflammation [50]. Third, a recently discovered population of macrophages associated with fibrosis has been shown to exhibit elevated expression of Spp1 (Spp1 ${}^{+}$${}^{+}$^(+){ }^{+}). These macrophages exhibit increased proliferation in the lung tissue of patients with IPF compared to healthy individuals [68]. OPN secreted by these macrophages accumulates in and around fibroblastic lesions composed of myofibroblasts, thereby contributing to the activation of myofibroblasts in lung fibrosis [68]. Spp1 ${}^{+}$${}^{+}$^(+){ }^{+}macrophages have been shown to proliferate in various organs, including the liver, kidney, heart, and lungs, and they play a role in the progression of organ fibrosis [68-70]. Fourth, OPN acts on neighbouring macrophages in an autocrine or paracrine manner, leading to their polarization into the profibrotic phenotype (M2) via activation of the Janus kinase 2 (JAK2)/signal transducers and activators of transcription 3 (STAT3) signalling pathway, thereby promoting the progression of pulmonary fibrosis [71].
几项研究揭示了 OPN 与肺纤维化中免疫细胞之间的联系。首先,OPN 在布洛菌(BLM)诱导的肺炎和肺纤维化中发挥作用,影响致病性 IL-17/保护性 IFN-γ T 细胞比例[67]。其次,致病性记忆 Th2 细胞在哮喘的气道纤维化过程中产生扩张素;扩张素介导的信号传导直接重编程嗜酸性粒细胞呈炎症状态,并促进 OPN 的产生,从而引发嗜酸性粒细胞介导的气道炎症性纤维化反应[50]。第三,最近发现与纤维化相关的巨噬细胞群体表现出 Spp1 基因(编码 OPN 蛋白)的高表达。与健康人相比,这些巨噬细胞在特发性肺纤维化患者的肺组织中增殖明显[68]。这些巨噬细胞分泌的 OPN 蛋白积累在由肌纤维细胞组成的纤维化病灶及周围,从而促进肺纤维化中肌纤维细胞的活化[68]。Spp1 基因高表达的巨噬细胞在肝脏、肾脏、心脏和肺等器官中均有增殖,并参与器官纤维化的进程[68-70]。第四,OPN 通过自分泌或旁分泌方式作用于邻近的巨噬细胞,激活 JAK2/STAT3 信号通路,将其极化为促纤维化表型(M2),从而促进肺纤维化的发展[71]。

In lung fibrosis associated with systemic sclerosis (SSc), the secretion
在与系统性硬化相关的肺纤维化中,分泌

Fig. 3. Role of OPN in fibrotic diseases. In fibrotic diseases, OPN induces the migration, adhesion, differentiation, activation and proliferation of macrophages, fibroblasts, myofibroblasts and other cells, which produce and deposit ECM and promote the occurrence and development of fibrosis. Note: Solid lines indicate experimentally confirmed mechanisms. Dashed lines indicate mechanisms that are under investigation. Here, we show the involvement of OPN/Spp1 and its downstream targets in lungs, liver, kidney and heart fibrosis. The figure was produced using Servier Medical Art (http://www.servier.com). Abbreviations: AC, acetylation; AKT, protein kinase B; AP-1, activator Protein-1; $\alpha$$\alpha$alpha\alpha-SMA, a-smooth muscle actin; $\beta 2$$\beta 2$beta2\beta 2 AR, $\beta 2$$\beta 2$beta2\beta 2 adrenergic receptor; cAMP, cyclic 3, 5 -adenosine monophosphate; COL-I, type I collagen; ECM, extracellular matrix; EMT, epithelial-mesenchymal transition; Epac1, exchange protein directly activated by cAMP-1; ERK, extracellular regulated protein kinases; FN, fibronectin; FOX3a, forkhead box O3a; HDAC1/2, histone deacetylases 1/2; HMGB1, high-mobility group box-1; HSCs, hepatic stellate cells; IFN- $\gamma$$\gamma$gamma\gamma, interferon- $\gamma$$\gamma$gamma\gamma; FMT, fibroblast-to-myofibroblast transition; GSK-3ß, glycogen synthase kinase-3ß; IL-6, interleukin-6; IL-17, interleukin-17; JAK2, janus kinase 2; M1, classically activated macrophages; M2, alternatively activated macrophages; MAPK, mitogen-activated protein kinase; MMP-2, matrix metalloproteinase-2; NF-кB, nuclear factor kappa B; N-OPN, N-terminal fragment; NOX, NADPH oxidase; OPN, osteopontin; pAKT, phosphorylated protein kinase B; PAI-1, plasminogen activator inhibitor-1; PI3K, phosphoinositide 3-kinase; PTEN, Phosphatase and Tensin Homologue; Shh, sonic hedgehog; Smad, small mother against decapentaplegic; STATA3, signal transducers and activators of transcription 3; TGF- $\beta 1$$\beta 1$beta1\beta 1, transforming growth factor- $\beta 1$$\beta 1$beta1\beta 1; TIMP-1, tissue inhibitor of metal-loprotease-1.
图 3. OPN 在纤维化疾病中的作用。在纤维化疾病中,OPN 诱导巨噬细胞、成纤维细胞、肌纤维细胞和其他细胞的迁移、粘附、分化、激活和增殖,这些细胞产生和沉积细胞外基质,促进纤维化的发生和发展。注意:实线表示实验证实的机制,虚线表示正在研究中的机制。在这里,我们展示了 OPN/Spp1 及其在肺、肝、肾和心脏纤维化中的下游靶点的参与。该图使用 Servier Medical Art 制作(http://www.servier.com)。 缩写：AC,乙酰化；AKT,蛋白激酶 B；AP-1,激活蛋白-1；α-SMA,α-平滑肌肌动蛋白；AR,肾上腺素受体；cAMP,环腺苷酸 3',5'-单磷酸；COL-I,I 型胶原；ECM,细胞外基质；EMT,上皮间质转化；Epac1,直接被 cAMP 激活的交换蛋白 1；ERK,细胞外调节蛋白激酶；FN,纤维连接蛋白；FOXO3a,叉头盒蛋白 O3a；HDAC1/2,组蛋白去乙酰化酶 1/2；HMGB1,高迁移率族蛋白盒-1；HSCs,肝星状细胞；IFN-γ,干扰素-γ；FMT,成纤维细胞向肌成纤维细胞转化；GSK-3β,糖原合酶激酶-3β；IL-6,白细胞介素-6；IL-17,白细胞介素-17；JAK2,anus 激酶 2；M1,经典激活巨噬细胞；M2,替代激活巨噬细胞；MAPK,丝裂原活化蛋白激酶；MMP-2,基质金属蛋白酶-2；NF-κB,核因子-κB；N-OPN,N 端片段；NOX,NADPH 氧化酶；OPN,骨桥蛋白；pAKT,磷酸化蛋白激酶 B；PAI-1,纤溶酶激活物抑制剂-1；PI3K,磷酯酶 3 激酶；PTEN,磷酸酶和张力蛋白同源物；Shh,声波趣旨素；Smad,小母反刍分裂蛋白；STAT3,信号转导和转录激活因子 3；TGF-β,转化生长因子-β；TIMP-1,金属蛋白酶抑制剂-1。
of OPN by macrophages plays a role in tissue remodelling by sensitizing and mobilizing fibroblasts in response to other fibrogenic growth factors, thereby contributing to the progression of fibrosis [52]. Multiwalled carbon nanotubes (MWCNTs) and single-walled carbon nanotubes (SWCNTs) can induce pulmonary fibrosis. OPN plays a role in initiating cellular mechanisms leading to SWCNT-induced pulmonary fibrosis upstream of TGF- $\beta 1$$\beta 1$beta1\beta 1 [61]. MWCNTs significantly induce OPN expression to activate the small mother against decapentaplegic (Smad)-dependent TGF- $\beta 1$$\beta 1$beta1\beta 1 signalling pathway and promote the transformation and functionalization of myofibroblasts [60]. Additionally, OPN has been associated with enhanced fibroblast migration and the enlargement of fibrotic foci through increased IL-6 secretion mediated by the extracellular signal-regulated kinase (ERK) pathway [72].
巨噬细胞分泌的 OPN 在纤维化进程中发挥作用,通过增强其对其他纤维化生长因子的敏感性和迁移性来调节成纤维细胞,从而推动了纤维化的发展[52]。多壁碳纳米管(MWCNTs)和单壁碳纳米管(SWCNTs)可诱导肺纤维化。OPN 在启动导致 SWCNT 诱导的肺纤维化的细胞机制中起作用,位于 TGF- $\beta 1$$\beta 1$beta1\beta 1 之上[61]。MWCNTs 显著诱导 OPN 表达,激活 Smad 依赖的 TGF- $\beta 1$$\beta 1$beta1\beta 1 信号通路并促进肌成纤维细胞的转化和功能化[60]。此外,OPN 还与增强纤维细胞迁移和纤维灶的扩大有关,这是通过 ERK 通路介导的 IL-6 分泌增加所致[72]。

The differentiation of myofibroblasts involves multiple sources. Several different myofibroblast origin hypotheses have been proposed, and includes fibroblast-to-myofibroblast transition (FMT), endothelial-to-mesenchymal transition, and epithelial-mesenchymal transition (EMT). Silicosis, a systemic disease caused by crystalline silica, results in diffuse lung fibrosis. A study showed that exposure to silica increased the expression of OPN/Spp1 in macrophages and exosomes [73]. Inhibiting exosomal OPN/Spp1 derived from macrophages has been shown to suppress FMT [73]. Furthermore, Hatipoglu et al. [62]
成纤维细胞向肌成纤维细胞的转化涉及多种来源。已提出几种不同的肌成纤维细胞起源假说,包括成纤维细胞向肌成纤维细胞的转化(FMT)、内皮间质转化和上皮间质转化(EMT)。硅尘肺是由结晶硅引起的系统性疾病,导致弥漫性肺纤维化。一项研究显示,暴露于硅粉会增加巨噬细胞和外泌体中 OPN/Spp1 的表达[73]。抑制来自巨噬细胞的外泌体 OPN/Spp1 可抑制 FMT[73]。此外,Hatipoglu 等人[62]
demonstrated the attenuation of lung fibrosis by targeting EMT in a mouse model of BLM-induced pulmonary fibrosis. This effect was achieved by using a small interfering RNA (siRNA) to specifically reduce OPN expression [62]. The macrophage-myofibroblast transition (MMT) pathway is a newly discovered pathway of myofibroblast transdifferentiation that was initially identified in renal fibrosis [74]. Our recent unpublished research provided evidence of the involvement of the MMT pathway in the development of pulmonary fibrosis in humans and established animal models. In the BLM-induced pulmonary fibrosis mouse model, MMT cells were identified and labelled by immunofluorescence staining and flow cytometry, confirming that they were the primary sources of myofibroblasts. OPN plays a regulatory role in MMT-related lung fibrosis in vitro and in vivo.
在一个 BLM 诱导的肺纤维化小鼠模型中,通过靶向 EMT 来减轻肺纤维化。这一效果是通过使用小干扰 RNA(siRNA)来特异性降低 OPN 表达实现的[62]。巨噬细胞-肌纤维细胞转化(MMT)通路是一种新发现的肌纤维细胞转分化通路,最初是在肾纤维化中发现的[74]。我们最近未发表的研究证明了 MMT 通路在人类肺纤维化以及建立的动物模型中的参与。在 BLM 诱导的肺纤维化小鼠模型中,通过免疫荧光染色和流式细胞术鉴定和标记了 MMT 细胞,证实它们是肌纤维细胞的主要来源。OPN 在体外和体内调节与 MMT 相关的肺纤维化。

The characteristic of liver fibrosis is that hepatic stellate cells (HSCs) transform into myofibroblasts, resulting in the excessive deposition of ECM, which is known as HSCs activation [75]. OPN is a crucial signalling molecule that mediates this activation process. In 2012, Urtasun et al. demonstrated that mice overexpressing the OPN gene
肝纤维化的特征是肝星状细胞(HSCs)转化为肌纤维细胞,导致细胞外基质(ECM)过度沉积,即所谓的 HSCs 激活[75]。OPN 是一种关键的信号分子,介导了这一激活过程。2012 年,Urtasun 等人证明了过度表达 OPN 基因的小鼠

Table 1  表 1
Overview of OPN/Spp1 in lung fibrosis.
肺纤维化中 OPN/Spp1 的概述。

Abbreviations: BALF, bronchoalveolar lavage fluid; BLM, bleomycin; COL-I, type I collagen; EMT, epithelial-mesenchymal transition; ERK, extracellular regulated protein kinases; FMT, fibroblasts-to-myofibroblasts transition; IFN- $\gamma$$\gamma$gamma\gamma, interferon- $\gamma$$\gamma$gamma\gamma; IL-6, interleukin-6; IL-17, interleukin-17; IL-33, interleukin-33; IPF, idiopathic pulmonary fibrosis; JAK2, Janus kinase 2; MMP-1, matrix metalloproteinase-1; MMP-2, matrix metalloproteinase-2; MMP-7, matrix metalloproteinase-7; MWCNTs, multi-walled carbon nanotubes; NHLFs, human-derived lung fibroblasts; OPN, osteopontin; OPN ${}^{-/}$${}^{-/}$^(-//){ }^{-/}, OPN knockout; PaO 2 , arterial oxygen tension; PDIA3, protein disulfide isomerases A3; Smad, small mother against decapentaplegic; Spp1, secreted phosphoprotein 1; SSc, systemic sclerosis; STAT3, signal transducers and activators of transcription 3; SWCNT, single-walled carbon nanotubes; TGF- $\beta 1$$\beta 1$beta1\beta 1, transforming growth factor- $\beta 1$$\beta 1$beta1\beta 1; TIMP-1, tissue inhibitor of metalloprotease-1; UIP, usual interstitial pneumonitis; NA, not applicable.
缩写:BALF,支气管肺泡灌洗液;BLM,博来霉素;COL-I,I 型胶原蛋白;EMT,上皮-间质转化;ERK,细胞外调节蛋白激酶;FMT,成纤维细胞向肌成纤维细胞转化;IFN-γ,干扰素-γ;IL-6,白细胞介素-6;IL-17,白细胞介素-17;IL-33,白细胞介素-33;IPF,特发性肺纤维化;JAK2,Janus 激酶 2;MMP-1,基质金属蛋白酶-1;MMP-2,基质金属蛋白酶-2;MMP-7,基质金属蛋白酶-7;MWCNTs,多壁碳纳米管;NHLFs,人源肺成纤维细胞;OPN,骨桥蛋白;OPN-/-,OPN 敲除;PaO2,动脉血氧分压;PDIA3,蛋白二硫键异构酶 A3;Smad,小母亲反装式;Spp1,分泌性磷蛋白 1;SSc,系统性硬化症;STAT3,信号转导和转录激活因子 3;SWCNT,单壁碳纳米管;TGF-β,转化生长因子-β;TIMP-1,金属蛋白酶抑制剂-1;UIP,常见间质性肺炎;NA,不适用。
spontaneously developed liver fibrosis; HSCs isolated from wild-type (WT) mice exhibited a more profibrogenic phenotype than those from ${\mathrm{OPN}}^{-/-}$${\mathrm{OPN}}^{-/-}$OPN^(-//-)\mathrm{OPN}^{-/-}mice [76]. This effect was mediated by activation of the phosphoinositide 3-kinase (PI3K)/phosphorylated protein kinase B (pAkt)/nuclear factor kappa B (NF-кB) signalling pathway, which was triggered by the interaction between OPN and $\alpha \mathrm{v}\beta 3$$\alpha \mathrm{v}\beta 3$alphavbeta3\alpha \mathrm{v} \beta 3 integrin on the surface of HSCs [76]. This interaction led to the upregulation of collagen type I (COL-I) and the subsequent development of fibrosis [76].
自发发展的肝脏纤维化;从野生型(WT)小鼠分离的肝星状细胞表现出比从 ${\mathrm{OPN}}^{-/-}$${\mathrm{OPN}}^{-/-}$OPN^(-//-)\mathrm{OPN}^{-/-} 小鼠更有促纤维化表型[76]。这种作用是通过激活磷酸肌醇 3-激酶(PI3K)/磷酸化蛋白激酶 B(pAkt)/核因子κB(NF-κB)信号通路介导的,这种通路是由 OPN 与 HSCs 表面的 $\alpha \mathrm{v}\beta 3$$\alpha \mathrm{v}\beta 3$alphavbeta3\alpha \mathrm{v} \beta 3 整合素的相互作用触发的[76]。这种相互作用导致 1 型胶原(COL-I)的上调和随后的纤维化发展[76]。

In a subsequent study, OPN was shown to be upstream of highmobility group box-1 (HMGB1), a damage-associated molecular pattern involved in liver fibrosis [77]. In vitro, recombinant human OPN (rOPN) induced HMGB1 expression and translocation in primary rat HSCs, contributing to the increase in COL-I production [77]. Mechanistically, rOPN induced the acetylation (AC) of HMGB1 in HSCs due to an increase in NADPH oxidase (NOX) activity and an associated decrease in histone deacetylases $1/2$$1/2$1//21 / 2 (HDAC1/2), leading to the upregulation of COL-I [77]. Some studies have revealed that HSCs have increased production of COL-I through an OPN-TGF- $\beta 1$$\beta 1$beta1\beta 1-dependent pathway [78,79]. Furthermore, OPN inhibited miR-129-5p expression, thereby activating HSCs and promoting COL-I expression [80]. Notably, thrombin-cleaved
在随后的研究中,发现 OPN 位于高迁移率族蛋白盒-1(HMGB1)的上游,HMGB1 是一种与肝纤维化相关的损伤相关分子模式[77]。体外实验中,重组人 OPN(rOPN)诱导了主要大鼠肝星状细胞(HSCs)中 HMGB1 的表达和转位,从而增加了 I 型胶原(COL-I)的产生[77]。从机理上看,rOPN 诱导 HSCs 中 HMGB1 乙酰化,这是由于 NADPH 氧化酶(NOX)活性的增加以及组蛋白去乙酰化酶(HDAC1/2)活性的降低,从而导致 COL-I 的上调[77]。一些研究表明,HSCs 通过一条 OPN-TGF-β依赖性通路增加了 COL-I 的产生[78,79]。此外,OPN 抑制了 miR-129-5p 的表达,从而激活 HSCs 并促进 COL-I 的表达[80]。值得注意的是,凝血酶切割的

OPN but not full-length OPN was shown to promote HSCs activation, proliferation, and migration by $\alpha 4\beta 1$$\alpha 4\beta 1$alpha4beta1\alpha 4 \beta 1 and $\alpha 9\beta 1$$\alpha 9\beta 1$alpha9beta1\alpha 9 \beta 1 integrins via the mito-gen-activated protein kinase (MAPK) and NF-кB signalling pathways [81].
截短型 OPN 而非完整长度 OPN 已被证明通过 $\alpha 4\beta 1$$\alpha 4\beta 1$alpha4beta1\alpha 4 \beta 1 和 $\alpha 9\beta 1$$\alpha 9\beta 1$alpha9beta1\alpha 9 \beta 1 整合素促进造血干细胞的激活、增殖和迁移,涉及丝裂原活化蛋白激酶(MAPK)和 NF-кB 信号通路[81]。

OPN stimulates the development of kidney tubulointerstitial fibrosis by promoting the infiltration of macrophages. Studies have shown that ${\mathrm{OPN}}^{-/-}$${\mathrm{OPN}}^{-/-}$OPN^(-//-)\mathrm{OPN}^{-/-}mice subjected to unilateral ureteral obstruction (UUO) exhibit reduced macrophage influx, collagen deposition, and TGF- $\beta 1\mathrm{mRNA}$$\beta 1\mathrm{mRNA}$beta1mRNA\beta 1 \mathrm{mRNA} expression compared to WT mice [82,83]. A separate study discovered that MMP-9-cleaved OPN enhanced macrophage Transwell migration [84]. Inhibiting MMP-9 significantly reduced MMP-9-cleaved OPN levels and decreased macrophage infiltration and renal fibrosis in the kidneys of UUO mice [84].
OPN 刺激宏噬细胞的浸润,促进肾小管间质纤维化的发展。研究表明,经单侧输尿管梗阻(UUO)处理的 ${\mathrm{OPN}}^{-/-}$${\mathrm{OPN}}^{-/-}$OPN^(-//-)\mathrm{OPN}^{-/-} 小鼠,与野生型小鼠相比,宏噬细胞侵润、胶原沉积和 TGF- $\beta 1\mathrm{mRNA}$$\beta 1\mathrm{mRNA}$beta1mRNA\beta 1 \mathrm{mRNA} 表达均有所降低[82,83]。另一项研究发现,MMP-9 裂解的 OPN 增强了宏噬细胞穿过 Transwell 膜的迁移[84]。抑制 MMP-9 明显降低了 MMP-9 裂解的 OPN 水平,并减少了 UUO 小鼠肾脏中的宏噬细胞浸润和肾纤维化[84]。

In an aldosterone-induced animal model of renal fibrosis, OPN expression is transcriptionally regulated by aldosterone through mineralocorticoid receptors. OPN deficiency protects against aldosterone-induced inflammation, oxidative stress, and interstitial fibrosis in the kidney [85]. In angiotensin II-induced renal injury, OPN
在一种醛固酮诱导的肾纤维化动物模型中,OPN 表达受醛固酮通过矿物质皮质激素受体的转录调控。OPN 缺乏可以保护肾脏免受醛固酮诱导的炎症、氧化应激和间质性纤维化[85]。在血管紧张素 II 诱导的肾损伤中,OPN

Table 2  表格 2
Overview of OPN/Spp1 in other fibrotic diseases.
关于 OPN/Spp1 在其他纤维化疾病中的概述。

Table 2 (continued)  表 2（续）

factor- $\beta$$\beta$beta\beta; TGF- $\beta 1$$\beta 1$beta1\beta 1, transforming growth factor- $\beta 1$$\beta 1$beta1\beta 1; UUO, unilateral ureteral obstruction; NA, not applicable.
因子- $\beta$$\beta$beta\beta ; TGF- $\beta 1$$\beta 1$beta1\beta 1 , 转化生长因子- $\beta 1$$\beta 1$beta1\beta 1 ; UUO, 单侧输尿管阻塞; NA, 不适用.
modulates renal tissue fibrosis by regulating profibrotic cytokines [86].
通过调节促纤维化细胞因子调节肾组织纤维化[86]。
OPN has also been implicated as an activator of (myo)fibroblasts in kidney fibrosis. In a recent study published in 2022, it was observed that OPN, particularly its N-terminal fragment ( $\mathrm{N}-\mathrm{OPN}$$\mathrm{N}-\mathrm{OPN}$N-OPN\mathrm{N}-\mathrm{OPN} ), was upregulated in various models of chronic kidney disease (CKD) and could be encapsulated by tubular exosomes [87]. Subsequently, OPN and N-OPN in tubular cell-derived exosomes were transferred to fibroblasts, where they bound with CD44 and promoted fibroblast proliferation and activation [87]. Moreover, OPN has been shown to promote EMT, which is involved in the differentiation and activation of (myo)fibroblasts [85, 88].
骨粉蛋白(OPN)也被认为是肾脏纤维化过程中(肌纤维细胞)纤维细胞的激活剂。在 2022 年发表的一项最新研究中,观察到 OPN,特别是其 N 端片段( $\mathrm{N}-\mathrm{OPN}$$\mathrm{N}-\mathrm{OPN}$N-OPN\mathrm{N}-\mathrm{OPN} ),在各种慢性肾病(CKD)模型中呈上调表达,并可被肾小管外泌体所包裹[87]。随后,肾小管细胞来源的外泌体中的 OPN 和 N 端 OPN 被转移到纤维细胞中,它们与 CD44 结合,促进了纤维细胞的增殖和激活[87]。此外,OPN 还被证明可促进上皮间质转化(EMT),而这种转化过程参与了(肌纤维细胞)纤维细胞的分化和激活[85,88]。

In Cardiac fibrosis, OPN is mainly associated with the activation of cardiac fibroblasts. In 2015, Lorenzen’s group showed that OPN activated activator protein-1 (AP-1)-mediated miR-21 transcription, resulting in subsequent profibrotic effects by targeting phosphatase and tensin homologue (PTEN)/Smad7 and ultimately activating WT fibroblasts [89]. OPN could induce atrial fibrosis in a dose- and
在心肌纤维化中,OPN 主要与心肌成纤维细胞的激活有关。2015 年,Lorenzen 小组发现,OPN 激活激活蛋白-1(AP-1)介导的 miR-21 转录,进而通过靶向磷酸酶和张力同源物(PTEN)/Smad7 而产生顺向纤维化效应,最终激活成纤维细胞[89]。OPN 可以剂量和时间依赖性地引起房颤纤维化。
time-dependent manner. In vitro studies of cultured human atrial fibroblasts (hAFs), shown that OPN activated the protein kinase B (Akt)/glycogen synthase kinase-3 $\beta$$\beta$beta\beta (GSK-3 $\beta$$\beta$beta\beta )/ $\beta$$\beta$beta\beta-catenin signalling pathway and suppressed autophagy, which synergistically promoted the activation of hAFs [90].
时间依赖性方式。体外培养的人心房成纤维细胞(hAFs)研究表明,OPN 激活了蛋白激酶 B(Akt)/糖原合成酶激酶-3(GSK-3)/β-catenin 信号通路,并抑制了自噬,这种协同促进了 hAFs 的激活[90]。

Additionally, in H9c2 cardiac cells treated with mineralocorticoids, OPN promoted cardiac fibrosis by directly inhibiting the effect of the antifibrotic cardiac $\beta 2$$\beta 2$beta2\beta 2-adrenergic receptor (AR) signalling via cyclic 3,5adenosine monophosphate (cAMP)/exchange protein directly activated by cAMP (Epac)-1 [91].
此外，在经过矿物皮质激素处理的 H9c2 心肌细胞中，OPN 通过直接抑制抗纤维化心脏β-肾上腺素能受体(AR)信号通路中的环腺苷酸 3,5-单磷酸(cAMP)/直接通过 cAMP 激活的交换蛋白(Epac)-1 来促进心肌纤维化[91]。

Several studies have suggested that the profibrotic effects of OPN on the heart may be closely related to prothrombin-mediated cleavage of OPN. In pressure-overloaded mouse heart model, full-length OPN was increased in left ventricular tissue during the early phase after pressure overload; however, OPN did not induce COL-I expression unless it was cleaved by thrombin [92]. After being cleaved by thrombin, a specific peptide sequence on the N-terminal fragment of OPN (RGDSLAYGLR) is exposed, and treatment of cardiac fibroblasts with N-OPN or this specific peptide sequence induces COL-I expression [92]. In contrast, when the
几项研究已经表明,OPN 对心脏的促纤维化效应可能与凝血酶介导的 OPN 裂解密切相关。在压力过负荷的小鼠心脏模型中,全长 OPN 在压力过负荷后的早期阶段在左心室组织中增加;然而,除非被凝血酶裂解,否则 OPN 不会诱导 COL-I 表达[92]。经凝血酶裂解后,OPN N 端片段上特定的肽序列(RGDSLAYGLR)被暴露,用 N-OPN 或此特定肽序列处理心脏成纤维细胞可诱导 COL-I 表达[92]。相比之下,当 N 端片段被去除时,OPN 失去了诱导 COL-I 表达的能力。

N-terminal OPN fragment lacked the SVVYGLR sequence, the C-terminal fragment did not produce these effects [93]. Notably, a sustained-release gel containing an OPN fragment or SVVYGLR peptide was successfully transplanted into a rat model of ischaemic cardiomyopathy and significantly improved cardiac function [93]. This improvement can be attributed to the activation of fibroblasts, which promotes the production of collagen proteins, particularly collagen type III, providing elasticity to the fibrotic myocardium and consequently improving cardiac function [93]. This finding is consistent with previous results [94-98], which suggest that the role of OPN as a double-edged sword after cardiac injury events and its negative role in tissue remodelling may not be fully justified. Instead, preserving appropriate OPN expression rather than completely inhibiting it during cardiac remodelling might be more beneficial for patient prognosis.
N 端 OPN 片段缺乏 SVVYGLR 序列,C 端片段未产生这些效果[93]。值得注意的是,包含 OPN 片段或 SVVYGLR 肽的缓释凝胶成功移植到大鼠缺血性心肌病模型中,显著改善了心脏功能[93]。这种改善可归因于成纤维细胞的激活,促进了胶原蛋白(尤其是 III 型胶原)的产生,为纤维化心肌提供弹性,从而改善心脏功能[93]。这一发现与之前的结果一致[94-98],表明 OPN 作为伤心事件之后的双刃剑作用以及其在组织重塑中的负面作用并非完全成立。相反,在心脏重塑期间保留适度的 OPN 表达而非完全抑制可能对患者预后更有益。

In skin fibrosis, OPN is thought to stimulate fibroblasts during the early stages of their differentiation into myofibroblasts [40,99]. OPN was upregulated in SSc skin in a study that used microarray analyses to compare SSc skin and healthy control skin [100]. A follow-up study demonstrated that OPN was localized to dermal fibroblasts and infiltrating inflammatory cells in the skin of patients with SSc. OPN ${}^{-/-}$${}^{-/-}$^(-//-){ }^{-/-}mice have decreased dermal thickness and dermal fibrosis compared with WT mice challenged with subcutaneous BLM, which may involve the modulation of TGF- $\beta$$\beta$beta\beta production [101]. Cheng et al. used R language and bioinformatics to show that miR-27a-3p was reduced in the skin tissues of patients with SSc [102]. MiR-27a-3p exerts antifibrotic effects by negatively regulating Spp1 and ERK signalling and is more prominent in fibroblasts than in other cells [102]. Furthermore, in human keloids, OPN immunoreactivity can be observed throughout the epidermis, mononuclear cells, and scattered fibroblasts [103]. Macrophage-secreted OPN stimulates collagen triple helix repeat containing 1 (CTHRC1) ${}^{+}$${}^{+}$^(+){ }^{+}fibroblasts to induce excessive collagen deposition in keloids [104].
在皮肤纤维化中,认为 OPN 可刺激成纤维细胞在向肌成纤维细胞分化的早期阶段[40,99]。一项使用基因芯片分析比较硬皮病皮肤和健康对照皮肤的研究发现,OPN 在硬皮病皮肤中表达上调[100]。后续研究证明,OPN 定位于硬皮病患者皮肤中的真皮成纤维细胞和浸润性炎症细胞。OPN 敲除小鼠与野生型小鼠相比,在皮下 BLM 诱导的条件下,真皮厚度和真皮纤维化均降低,这可能涉及对 TGF-β生产的调节[101]。Cheng 等人使用 R 语言和生物信息学方法显示,miR-27a-3p 在硬皮病患者皮肤组织中表达降低[102]。miR-27a-3p 通过负调控 Spp1 和 ERK 信号传导发挥抗纤维化作用,在成纤维细胞中比其他细胞更为突出[102]。此外,在人类瘢痕中,OPN 免疫反应可观察到遍布表皮、单核细胞和散布的成纤维细胞[103]。来自巨噬细胞分泌的 OPN 刺激胶原三螺旋重复含 1(CTHRC1)阳性成纤维细胞诱导瘢痕中过度的胶原沉积[104]。

During the early stage of prostatic hyperplasia, macrophages, prostatic stromal cells, and epithelial cells can serve as sources of OPN [105]. OPN drives the expression of multiple cytokines and chemokines within prostate stromal cells, thereby promoting fibrogenesis [105]. OPN deficiency decreases inflammation and fibrosis and prevents urinary dysfunction [106]. Moreover, it has been reported that OPN may be involved in prostatic inflammation and fibrosis induced by an oestrogen/androgen imbalance in rats [107].
在前列腺增生的早期阶段,巨噬细胞、前列腺间质细胞和上皮细胞可以作为 OPN 的来源 [105]。OPN 推动前列腺间质细胞中多种细胞因子和趋化因子的表达,从而促进纤维化过程 [105]。OPN 缺乏降低了炎症和纤维化,并防止了尿液功能障碍 [106]。此外,有报道称 OPN 可能参与了大鼠由雌雄激素失衡引起的前列腺炎症和纤维化 [107]。

PMF is a myeloproliferative neoplasm characterized by hyperplastic megakaryopoiesis and myelofibrosis. An earlier study by Rossella’s group revealed that overexpression of the transcription factor MAF contributes to PMF pathogenesis by driving the dysregulated production of OPN [108]. In vitro, OPN promoted proliferation and collagen production in fibroblasts and mesenchymal stromal cells [108]. Clinical relevance analyses showed increased plasma levels of OPN in PMF patients, and these levels were associated with more severe fibrosis and shorter overall survival [108]. Recently, Rossella’s group further elucidated the role of ERK1/2 signalling in supporting OPN production in myelofibrosis and demonstrated that OPN was a novel drug target in myelofibrosis based on inhibiting ERK1/2-driven OPN production or neutralizing OPN activity [109].
原发性骨髓纤维化(PMF)是一种骨髓增殖性肿瘤,其特点是巨核细胞生成过度和骨髓纤维化。Rossella 的研究小组在之前的研究中发现,转录因子 MAF 的过度表达通过驱动 OPN 的失调生产,从而促进了 PMF 的发生[108]。体外实验表明,OPN 促进成纤维细胞和间充质干细胞的增殖和胶原生产[108]。临床相关性分析显示,PMF 患者的血浆 OPN 水平升高,且这些水平与更严重的纤维化和更短的总生存期相关[108]。最近,Rossella 的研究小组进一步阐明了 ERK1/2 信号通路在支持骨髓纤维化中 OPN 产生的作用,并证明 OPN 是一种基于抑制 ERK1/2 驱动的 OPN 产生或中和 OPN 活性的新型靶向药物[109]。

Most patients with fibrosis are diagnosed at an advanced stage when the organ is severely damaged and has lost most of its physiological
大多数纤维化患者在器官严重受损、生理功能已大部分丧失的晚期才被诊断出来
function. The most trusted tool clinicians can use to assess the extent of organ fibrosis at any level is tissue biopsy, which, despite its overall safety, remains an invasive procedure that has some limitations. Therefore, identifying novel noninvasive biomarkers for early-stage organ fibrosis is critical. Furthermore, the assessment of fibrosis progression holds greater clinical value than the diagnosis of fibrosis itself. However, no sufficiently accurate biomarkers have been identified to date that reflect the activity/state of fibrosis. Another challenge lies in the lack of appropriate tools to efficiently and promptly evaluate the therapeutic efficacy of novel antifibrotic drugs. Thus, specific biomarkers are urgently needed for the timely diagnosis of fibrotic diseases, the prediction of disease progression, and the evaluation of clinical drug efficacy.
功能。临床医生用于评估任何级别器官纤维化程度的最可靠工具是组织活检,尽管总体上安全,但仍然是一种有一些局限性的侵入性操作。因此,找到新的非侵入性生物标志物以识别早期器官纤维化至关重要。此外,评估纤维化进展的临床价值大于纤维化本身的诊断。然而,迄今尚未发现足够准确的生物标志物能反映纤维化的活性/状态。另一个挑战在于缺乏有效和及时评估新型抗纤维化药物疗效的适当工具。因此,急需特定的生物标志物来及时诊断纤维化疾病、预测疾病进展和评估临床药物疗效。

The relatively increased levels of OPN in various fibrotic organs indicate that OPN is a potential biomarker of fibrosis. Several studies have consistently shown increased OPN levels in serum and body fluids during the early stages of organ fibrogenesis, establishing a positive correlation between OPN expression and organ fibrosis [52,87,108, 110-117]. These findings highlight the potential of OPN as a noninvasive early diagnostic tool for fibrotic diseases and for assessing fibrosis severity.
在各种纤维化器官中，相对较高的 OPN 水平表明 OPN 是潜在的纤维化生物标志物。几项研究一致显示,在器官纤维化的早期阶段,血清和体液中 OPN 水平增加,OPN 表达与器官纤维化呈正相关[52,87,108,110-117]。这些发现突出了 OPN 作为非侵入性早期诊断工具评估纤维化严重程度的潜能。

However, it is unlikely that a single biomarker can distinguish and predict the prognosis of fibrosis since numerous factors, which vary from patient-to-patient and disease-to-disease, are known to initiate and participate in the development of fibrosis. Therefore, a panel of multiple biomarkers is more likely to enhance the accuracy of fibrosis diagnosis and prognosis than a single biomarker, and the inclusion of OPN may provide crucial information in this regard. White E S and colleagues [118] reported that a combination of MMP-7, surfactant protein D (SP-D), and OPN concentrations demonstrated good performance in differentiating IPF from other forms of non-IPF interstitial lung disease (ILD). In IPF, a progression index based on four biomarkers (OPN, MMP-7, intercellular adhesion molecule-1, and periostin) was shown to be superior to the clinical GAP score (sex, age, and lung physiology) in predicting progression at 12 months [119]. Five genes, including Spp1, were shown to form an inflammation-hypoxia-related gene signature that accurately predicted the clinical outcome of patients with IPF [120]. To evaluate antifibrotic therapeutic efficacy, another study showed that cancer antigen 125 (CA-125), C-X-C motif chemokine 13 (CXCL13), MMP-7, SP-D, chitinase-3-like protein-1 (YKL-40), vascular cell adhesion protein-1 (VCAM-1), and OPN predicted differential transplant-free survival (TFS) in patients with IPF undergoing antifibrotic therapy, surpassing the thresholds observed in unexposed patients [121]. This finding suggests that composite clinical-molecular signatures, including OPN, can provide valuable information regarding outcome risk and treatment responses [121]. Further studies are required to validate these findings and definitively assess the utility of OPN as a biomarker of the treatment success of experimental antifibrotic therapies.
然而,由于已知许多从患者到患者、从疾病到疾病都不尽相同的因素参与并导致了肺纤维化的发生,单一的生物标志物很难明确区分和预测肺纤维化的预后。因此,使用多种生物标志物组合更可能提高肺纤维化诊断和预后的准确性,而包含骨桥素可能在这方面提供关键信息。White E S 等人[118]报告,MMP-7、肺表面活性物质 D(SP-D)和骨桥素浓度的组合在区分特发性肺纤维化和其他类型间质性肺病方面表现良好。在特发性肺纤维化中,基于四种生物标志物(骨桥素、MMP-7、细胞间黏附分子-1 和过氧蛋白)的进展指数被证明优于临床 GAP 评分(性别、年龄和肺功能)在预测 12 个月内的病情进展[119]。包括 Spp1 在内的五个基因被证明形成一个与炎症-缺氧相关的基因特征,能够准确预测特发性肺纤维化患者的临床结局[120]。为评估抗纤维化疗效,另一项研究显示,癌抗原 125(CA-125)、CXC 趋化因子 13(CXCL13)、MMP-7、SP-D、酷似白细胞 n-乙酰葫芦糖苷酶 3(YKL-40)、血管细胞粘附蛋白 1(VCAM-1)和骨桥素能够预测接受抗纤维化治疗的特发性肺纤维化患者的无移植生存期,优于未接受治疗患者的阈值[121]。这一发现表明,包括骨桥素在内的复合临床分子特征可以提供有关预后风险和治疗反应的有价值信息[121]。需要进一步研究来验证这些发现,并彻底评估骨桥素作为实验性抗纤维化疗法治疗成功的生物标志物的实用性。

As described previously, OPN may be a promising biomarker of various fibrotic diseases, as it is elevated in earlier stages of fibrosis and can help to identify high-risk individuals, assess fibrosis severity, closely monitor fibrosis progression, and evaluate the effectiveness and outcomes of disease treatment.
如前所述,OPN 可能是各种纤维化疾病的有希望的生物标志物,因为它在纤维化的早期阶段升高,可以帮助识别高危人群、评估纤维化的严重程度、密切监测纤维化的进展,以及评估疾病治疗的有效性和结果。

In conclusion, persistent or excessive expression of OPN is associated with fibroproliferation in various organs in laboratory animals and humans, such that its downregulation is a logical therapeutic objective. To our knowledge, no drug targeting the expression of OPN has entered clinical trials. However, a growing number of preclinical studies are underway.
总之，OPN 的持续或过度表达与实验动物和人类各种器官的纤维增殖相关,因此抑制其表达是一个合理的治疗目标。据我们所知,尚未有针对 OPN 表达的药物进入临床试验。但正在进行越来越多的临床前研究。

OPN blockade with OPN-neutralizing monoclonal antibodies or aptamers represents a promising approach for treating human fibrotic diseases. Therapeutic antibodies targeting OPN have shown
使用 OPN 中和单克隆抗体或适配体阻断 OPN 是治疗人类纤维化疾病的一种有前景的方法。针对 OPN 的治疗性抗体已显示出
effectiveness in various animal models of fibrotic diseases [109, 122-125]. However, pharmacokinetic and pharmacodynamic modelling and the simulation of different theoretical scenarios indicate that achieving sufficient target coverage using antibodies can be highly challenging primarily due to the rapid turnover of OPN and its relatively high plasma concentrations in humans [126]. Therefore, therapeutic antibodies against OPN must be engineered with significantly extended pharmacokinetics compared to conventional antibodies and administered at high doses with frequent dosing intervals [126].
在多种纤维化疾病动物模型中的有效性[109、122-125]。然而，药代动力学和药效动力学建模以及不同理论场景的模拟表明，主要由于 OPN 的快速转换和人体内相对较高的血浆浓度，使用抗体实现充分的靶点覆盖非常具有挑战性[126]。因此，针对 OPN 的治疗性抗体必须设计具有明显延长的药代动力学特性,相比于常规抗体,需要以较高剂量和频繁的给药间隔进行给药[126]。

OPN silencing holds promise as a therapeutic strategy for fibrotic diseases. In liver fibrosis, the delivery of siRNA-OPN via exosomes suppressed HSCs activation and ECM deposition, leading to improvements in liver function [127]. Similarly, OPN siRNA protected against BLM-induced pulmonary fibrosis in mice [62]. In terms of biotherapy, $\mathrm{CD}11{\mathrm{b}}^{+}\mathrm{CD}{14}^{+}$$\mathrm{CD}11{\mathrm{b}}^{+}\mathrm{CD}{14}^{+}$CD11b^(+)CD14^(+)\mathrm{CD} 11 \mathrm{~b}^{+} \mathrm{CD} 14^{+}monocyte transplantation could improve liver fibrosis by decreasing OPN levels [128].
抑制 OPN 转录持有治疗纤维化疾病的前景。在肝纤维化中,利用外泌体递送 siRNA-OPN 能抑制 HSC 激活和 ECM 沉积,从而改善肝功能[127]。同样地,OPN siRNA 能保护小鼠免受 BLM 诱导的肺纤维化[62]。就生物疗法而言, $\mathrm{CD}11{\mathrm{b}}^{+}\mathrm{CD}{14}^{+}$$\mathrm{CD}11{\mathrm{b}}^{+}\mathrm{CD}{14}^{+}$CD11b^(+)CD14^(+)\mathrm{CD} 11 \mathrm{~b}^{+} \mathrm{CD} 14^{+} 单核细胞移植可通过降低 OPN 水平改善肝纤维化[128]。

Chemical compounds or drugs can also protect against organ fibrosis by downregulating OPN expression. Epigallocatechin-3-gallate (EGCG), a polyphenol found in high concentrations in green tea and green tea extract, can inhibit OPN-dependent liver fibrosis by upregulating miR221 [129,130]. Mangiferin, a major glucoside of xanthone found in Rhizoma Anemarrhena, a well-known Chinese Materia Medica, has been shown to prevent renal glomerulus fibrosis in diabetic rats by suppressing OPN overproduction [131]. Additionally, certain existing drugs used in other fields, such as mesalazine [132-134], praziquantel [135], acetaminophen [136], amitriptyline [137], ramipril [138], cilostazol [139], triptolide and mycophenolate mofetil [140], may have potential as new antifibrotic agents due to their ability to lower OPN levels.
化学化合物或药物也可以通过下调 OPN 表达来保护器官免受纤维化。表明在绿茶和绿茶提取物中高度浓缩的儿茶素没食子酸(EGCG)可通过上调 miR221 来抑制 OPN 依赖性肝纤维化[129,130]。甘梨花苷是一种广泛存在于知名中药阿尼麻根中的主要黄酮衍生物,已被证明通过抑制 OPN 过度表达来预防糖尿病大鼠肾小球纤维化[131]。此外,某些现有的用于其他领域的药物,如美沙拉嗪[132-134]、吡喹酮[135]、对乙酰氨基酚[136]、阿米替林[137]、美托洛尔[138]、西洛他唑[139]、三必利和霉酚酸酯[140]也可能具有抗纤维化的潜力,因为它们能降低 OPN 水平。

Additionally, targeting the upstream regulators and downstream effectors of OPN may represent promising strategies to prevent fibrogenesis and associated adverse events. For example, OPN is upregulated in renal and cardiac fibrosis due to activation of the renin-angiotensinaldosterone system. Blocking the relevant mediators of OPN, such as mineralocorticoid receptor antagonism and aldosterone synthase inhibition, may offer benefits for heart and kidney fibrosis. However, this possibility remains open for research due to its complexity, but elucidating these mechanisms could have significant therapeutic potential.
此外，针对 OPN 的上游调节因子和下游效应因子可能代表预防纤维化及其相关不良事件的有希望的策略。例如，由于肾素-血管紧张素-醛固酮系统的激活,OPN 在肾脏和心脏纤维化中表达上调。阻断 OPN 的相关介质,如矿物皮质激素受体拮抗和醛固酮合成酶抑制,可能为心脏和肾脏纤维化带来益处。然而,由于其复杂性,这种可能性仍有待研究,但阐明这些机制可能具有重大治疗潜力。

Novel therapeutic strategies are urgently needed for fibrotic diseases. A growing number of studies have provided insights into the mechanisms and factors involved in regulating fibrosis associated with OPN. While OPN represents a potential target for fibrotic disease therapy, we still need to exercise caution for several reasons. First, the different forms of OPN may have distinct effects on fibrotic tissues (limited information is available), and fresh insights are needed to understand these variations and develop approaches to target specific OPN forms and activities in distinct organs and tissues. Second, some reports suggest that OPN improves organ function in some contexts (such as in cardiac fibrosis). Thus, it is essential to understand how and when the effects of OPN become beneficial or detrimental to the host by considering the various forms of OPN. Third, OPN is ubiquitous and has complex physiological functions, and it remains to be established whether suppressing OPN affects the physiological properties of the body. Finally, it has been shown that most of the biological activity of OPN resides in the N-terminal fragment. N-OPN may be an influential target in the fibrogenic mechanism of OPN compared to full-length OPN. Thus, preventing OPN cleavage may be more effective in treating fibrotic disease than inhibiting OPN production. More attention must be paid to this issue in future targeted studies. (Tables 1 and 2).
急需为纤维化疾病开发新的治疗策略。越来越多的研究提供了关于调节与 OPN 相关的纤维化的机理和因素的洞见。虽然 OPN 是纤维化疾病治疗的潜在靶标,但我们仍需谨慎考虑几方面问题。首先,不同形式的 OPN 可能对纤维化组织产生不同影响(目前信息有限),需要进一步深入理解这些差异,并制定方法靶向特定的 OPN 形式及其在不同器官和组织中的活性。其次,有报告称 OPN 在某些情况下(如心脏纤维化)可以改善器官功能。因此,需要理解 OPN 的作用何时有益,何时有害,需要全面考虑 OPN 的各种形式。第三,OPN 广泛存在且功能复杂,抑制 OPN 是否会影响机体的生理属性仍有待进一步确认。最后,已表明 OPN 的大部分生物活性在 N 端片段中,与全长 OPN 相比,N-OPN 可能是 OPN 纤维化机制的关键靶标。因此,阻止 OPN 裂解可能比抑制 OPN 生产更有效地治疗纤维化疾病。未来的靶向研究需要更多关注这一问题。

The studies involving animal participants (Fig. 2) were reviewed and approved by Sichuan University West China Hospital Health Research
涉及动物参与者的研究(图 2)已由四川大学华西医院健康研究伦理委员会审查批准。

Ethics (Project NO. 20220301141).
道德伦理学 (项目编号：20220301141)。

This work was supported by the $1\cdot 3.5$$1\cdot 3.5$1*3.51 \cdot 3.5 project for disciplines of excellence, West China Hospital, Sichuan University [grant numbers ZYJC18003]; and the development program of Sichuan province funding provided by Sichuan Science and Technology Department [Preject NO. 2021YFS0166].
该工作得到了 $1\cdot 3.5$$1\cdot 3.5$1*3.51 \cdot 3.5 学科卓越项目、四川大学华西医院[项目编号 ZYJC18003]以及四川省科技厅提供的四川省发展计划资金[项目编号 2021YFS0166]的支持。

Ziyi Tang: Conceptualization, Methodology, Data curation, Writingoriginal draft preparation. Zijing Xia: Conceptualization, Methodology, Funding acquisition, Writing-review and editing. Xiangpeng Wang: Validation. Yi Liu: Funding acquisition, Supervision. All authors approved the submitted final version.
汤紫怡:概念化、方法论、数据管理、原始稿件撰写。夏子景:概念化、方法论、获取资金、审阅与修订。王湘鹏:验证。刘毅:获取资金、监督。所有作者批准了提交的最终版本。

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
作者声明他们没有任何已知的竞争性的财务利益或可能影响本论文工作的个人关系。

We sincerely thank Servier Medical Art (http://www.servier.com) provides scientific material pictures.
我们衷心感谢 Servier 医学艺术(http://www.servier.com)提供科学材料图片。

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