title: Fibulin-4 reduces extracellular matrix production and suppresses chondrocyte differentiation via DKK1- mediated canonical Wnt/β-catenin signaling.
abstract: Fibulin-4 is an extracellular matrix (ECM) protein implicated in connective tissue development and elastic fiber formation. However, little is known about the underlying function of Fibulin-4 in cartilage development. The aim of this study was to investigate the role and probable mechanism of Fibulin-4 stimulation in ECM production and chondrocyte differentiation. Fibulin-4 has been observed to be abnormally elevated and matrix metalloproteinases 13 (MMP13) level was highly expressed in human osteoarthritis (OA) chondrocytes. In the chondrogenic cell line ATDC5, Fibulin-4 stimulation profoundly inhibited the expression of ECM gene type II collagen (Col2a1), aggrecan (Acan), and type X collagen (Col10a1). Overexpression of Fibulin-4 attenuated the expression of master transcription factors Sox6, Sox9 and Runx2, but had no effect on the expression of Sox5. Additionally, Fibulin-4 stimulation activated canonical Wnt pathway by reducing the expression of Wnt inhibitor DKK1 but not Sost. Moreover, Fibulin-4 augmented the expression of Wnt/β-catenin signaling target genes like β-catenin and Wnt-3a as well as diminished GSK-3β activation, and DKK1 abolished the effect of Fibulin-4 on chondrocyte differentiation, suggesting that Fibulin-4 is an important regulator of ECM production and chondrocyte differentiation through DKK1-mediated Wnt/β-catenin signaling. Our study provides evidence of a previously unknown link between Fibulin-4 and the canonical Wnt/β-catenin pathway that may contribute to our understanding of the molecular mechanisms of OA.
authors.affiliation: The Department of Orthopedics, Xinqiao Hospital, the Third Military Medical University, Chongqing 400037, PR China; The Department of Orthopedics, Xijing Hospital, the Fourth Military Medical University, Xi'an 710032, Shaanxi, PR China.
authors.forename: Lei
authors.initials: L
authors.lastname: Shangguan
authors.affiliation: The Department of Orthopedics, Xinqiao Hospital, the Third Military Medical University, Chongqing 400037, PR China.
authors.forename: Guangzhi
authors.initials: G
authors.lastname: Ning
authors.affiliation: The Department of Orthopedics, Xijing Hospital, the Fourth Military Medical University, Xi'an 710032, Shaanxi, PR China. Electronic address: zhoujingluozjl@163.com.
authors.forename: Zhuojing
authors.initials: Z
authors.lastname: Luo
authors.affiliation: The Department of Orthopedics, Xinqiao Hospital, the Third Military Medical University, Chongqing 400037, PR China. Electronic address: yuezhouxq@163.com.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhou
mesh_terms: D002356:Cartilage / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D019902:Chondrocytes / Q000166:cytology* / Q000473:pathology; D005109:Extracellular Matrix / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D010003:Osteoarthritis / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism; D060449:Wnt Signaling Pathway
chemical_list: C501126:DKK1 protein, human; C403672:EFEMP2 protein, human; D016326:Extracellular Matrix Proteins; D036341:Intercellular Signaling Peptides and Proteins; D014157:Transcription Factors
keywords: Chondrocyte differentiation; Fibulin-4; Wnt/β-catenin signaling