The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, No. 237 Luoyu Road, Wuhan, Hubei, 430079, China.
The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, No. 237 Luoyu Road, Wuhan, Hubei, 430079, China.
Biochim Biophys Acta Mol Cell Res. 2022 Sep;1869(9):119285. doi: 10.1016/j.bbamcr.2022.119285. Epub 2022 May 13.
Fibulin-3 is an extracellular matrix glycoprotein that is present in elastic tissue and involved in carcinoma development. Previous studies have indicated that fibulin-3 may affect skeletal development, cartilage, and osteoarthritis (OA). This study aims to investigate the function of fibulin-3 on chondrocytes under tumor necrosis factor alpha (TNF-α) stimulation and in murine OA models, and explore the possible mechanism. It was found that fibulin-3 was increased in the cartilage of OA models and in the chondrogenic cells ATDC5 stimulated by TNF-α. Fibulin-3 promoted the proliferation of ATDC5 cells both in the presence and absence of TNF-α. Moreover, overexpression of fibulin-3 suppressed the chondrogenic and hypertrophic differentiation of ATDC5 cells, while knockdown of fibulin-3 caused the opposite effect. Mechanistically, fibulin-3 partially suppressed the activation of TGF-β/Smad3 signaling by inhibiting the phosphorylation of Smad3. SIS3, a Smad3 inhibitor, decreased the chondrogenesis of articular cartilages in OA models, and partially reversed the chondrogenic differentiation of ATDC5 cells caused by knockdown of fibulin-3 in the presence of TNF-α. Furthermore, co-immunoprecipitation (Co-IP) showed that fibulin-3 could only interact with TGF-β type I receptor (TβRI), although overexpression of fibulin-3 reduced the protein levels of both TβRI and TβRII. In conclusion, this study indicates that fibulin-3 modulates the chondrogenic differentiation of ATDC5 cells in inflammation partially via TGF-β/Smad3 signaling pathway.
纤连蛋白-3 是一种细胞外基质糖蛋白，存在于弹性组织中，与癌的发生有关。先前的研究表明，纤连蛋白-3 可能影响骨骼发育、软骨和骨关节炎（OA）。本研究旨在探讨纤连蛋白-3 在肿瘤坏死因子-α（TNF-α）刺激下对软骨细胞的作用及其在鼠 OA 模型中的作用机制。结果发现，OA 模型软骨和 TNF-α刺激的软骨细胞系 ATDC5 中纤连蛋白-3 增加。纤连蛋白-3 促进 ATDC5 细胞在有无 TNF-α刺激的情况下增殖。此外，纤连蛋白-3 的过表达抑制 ATDC5 细胞的软骨形成和肥大分化，而纤连蛋白-3 的敲低则产生相反的效果。机制上，纤连蛋白-3 通过抑制 Smad3 的磷酸化，部分抑制 TGF-β/Smad3 信号通路的激活。Smad3 抑制剂 SIS3 降低 OA 模型关节软骨的软骨形成，并部分逆转 TNF-α存在时纤连蛋白-3 敲低引起的 ATDC5 细胞软骨形成分化。此外，免疫共沉淀（Co-IP）显示纤连蛋白-3 只能与 TGF-β Ⅰ型受体（TβRI）相互作用，尽管纤连蛋白-3 的过表达降低了 TβRI 和 TβRII 的蛋白水平。综上所述，本研究表明纤连蛋白-3 通过 TGF-β/Smad3 信号通路部分调节 ATDC5 细胞在炎症中的软骨形成分化。
