1. Academic Validation
  2. Fibulin-3 regulates the inhibitory effect of TNF-α on chondrocyte differentiation partially via the TGF-β/Smad3 signaling pathway

Fibulin-3 regulates the inhibitory effect of TNF-α on chondrocyte differentiation partially via the TGF-β/Smad3 signaling pathway

  • Biochim Biophys Acta Mol Cell Res. 2022 Sep;1869(9):119285. doi: 10.1016/j.bbamcr.2022.119285.
Xiaoxiao Xu 1 Chang Yang 1 Xijie Yu 1 Jiawei Wang 2
Affiliations

Affiliations

  • 1 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.
  • 2 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. Electronic address: wb000238@whu.edu.cn.
Abstract

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.

Keywords

Chondrocyte differentiation; Fibulin-3; Inflammation; Osteoarthritis; TGF-β/Smad3; TNF-α.

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