Sox4 is involved in osteoarthritic cartilage deterioration through induction of ADAMTS4 and ADAMTS5

Abstract

Osteoarthritis is a common disease in joint cartilages. Because the molecular pathogenesis of osteoarthritis remains elusive, early diagnostic markers and effective therapeutic agents have not been developed. To understand the molecular mechanisms, we attempted to identify transcription factors involved in the onset of osteoarthritis. Microarray analysis of mouse articular cartilage cells indicated that retinoic acid, a destructive stimulus in articular cartilage, up-regulated expression of sex-determining region Y-box (Sox)4, a SoxC family transcription factor, together with increases in Adamts4 and Adamts5, both of which are aggrecanases of articular cartilages. Overexpression of Sox4 induced a disintegrin-like and metallopeptidase with thrombospondin type 4 and 5 motif (ADAMTS4 and ADAMTS5, respectively) expression in chondrogenic cell lines C3H10T1/2 and SW1353. In addition, luciferase reporter and chromatin immunoprecipitation assays showed that Sox4 up-regulated ADAMTS4 and Adamts5 gene promoter activities by binding to their gene promoters. Another SoxC family member, Sox11, evoked similar effects. To evaluate the roles of Sox4 and Sox11 in articular cartilage destruction, we performed organ culture experiments using mouse femoral head cartilages. Sox4 and Sox11 adenovirus infections caused destruction of articular cartilage associated with increased Adamts5 expression. Finally, SOX4 and SOX11 mRNA expression was increased in cartilage of patients with osteoarthritis compared with nonosteoarthritic subjects. Thus, Sox4, and presumably Sox11, are involved in osteoarthritis onset by up-regulating ADAMTS4 and ADAMTS5.-Takahata, Y., Nakamura, E., Hata, K., Wakabayashi, M., Murakami, T., Wakamori, K., Yoshikawa, H., Matsuda, A., Fukui, N., Nishimura, R. Sox4 is involved in osteoarthritic cartilage deterioration through induction of ADAMTS4 and ADAMTS5.

A long non-coding RNA, HOTAIR, promotes cartilage degradation in osteoarthritis by inhibiting WIF-1 expression and activating Wnt pathway

“…To understand the link between HOTAIR and OA-related gene expression, we studied the effects of HOTAIR silencing and over-expression in chondrocytes by using SW1353 cells as an established chondrocytic cell model and a reliable transfection host (42). Although SW1353 is a chondrosarcoma cell line, the cells exhibit similar responses as primary chondrocytes to a variety of catabolic cytokines relevant to OA, and have been used as the cell line of choice in many studies to investigate the molecular mechanisms of OA pathogenesis (43)(44)(45). We found that HOTAIR over-expression in SW1353 cells matched the expression pro le of OA-related genes in human primary osteoarthritic chondrocytes, The roles of WIF-1 in skeletal tissue development has been investigated in other studies.…”

Role of Signal Transduction Pathways and Transcription Factors in Cartilage and Joint Diseases

“…In recent years, the unique features of articular chondrocytes compared with growth plate chondrocytes have begun to be elucidated, and the transcription factors involved in degradation of articular chondrocytes have been investigated. Although the SoxC family of transcription factors are important for endochondral ossification [65], two members, Sox4 and Sox11, were shown to be specifically upregulated by retinoic acid and IL-1 treatment in articular chondrocytes [66]. Sox4 and Sox11 upregulate expression of Adamts4 and Adamts5 by direct binding to their promoters [66].…”

“…Although the SoxC family of transcription factors are important for endochondral ossification [65], two members, Sox4 and Sox11, were shown to be specifically upregulated by retinoic acid and IL-1 treatment in articular chondrocytes [66]. Sox4 and Sox11 upregulate expression of Adamts4 and Adamts5 by direct binding to their promoters [66]. Overexpression of Sox4 and Sox11 also leads to the degradation of articular cartilage and increased expression of Adamts5 and MMP13 [66].…”

“…Sox4 and Sox11 upregulate expression of Adamts4 and Adamts5 by direct binding to their promoters [66]. Overexpression of Sox4 and Sox11 also leads to the degradation of articular cartilage and increased expression of Adamts5 and MMP13 [66]. Furthermore, expression of SOX4 and SOX11 was associated with the destruction of cartilage in patients with osteoarthritis [66], suggesting that the importance of these transcription factors in the onset and progression of osteoarthritis.…”

“…Overexpression of Sox4 and Sox11 also leads to the degradation of articular cartilage and increased expression of Adamts5 and MMP13 [66]. Furthermore, expression of SOX4 and SOX11 was associated with the destruction of cartilage in patients with osteoarthritis [66], suggesting that the importance of these transcription factors in the onset and progression of osteoarthritis. However, Sox11 has also been reported to regulate GDF5 expression in chondrogenic cell lines ATDC5 and C3H10T1/2 [67].…”