Osteoarthritis is the most common form of human arthritis. We investigated the potential role of asporin, an extracellular matrix component expressed abundantly in the articular cartilage of individuals with osteoarthritis, in the pathogenesis of osteoarthritis. Here we report a significant association between a polymorphism in the aspartic acid (D) repeat of the gene encoding asporin (ASPN) and osteoarthritis. In two independent populations of individuals with knee osteoarthritis, the D14 allele of ASPN is over-represented relative to the common D13 allele, and its frequency increases with disease severity. The D14 allele is also over-represented in individuals with hip osteoarthritis. Asporin suppresses TGF-β–mediated expression of the genes aggrecan (AGC1) and type II collagen (COL2A1) and reduced proteoglycan accumulation in an in vitro model of chondrogenesis. The effect on TGF-β activity is allele-specific, with the D14 allele resulting in greater inhibition than other alleles. In vitro binding assays showed a direct interaction between asporin and TGF-β. Taken together, these findings provide another functional link between extracellular matrix proteins, TGF-β activity and disease, suggesting new therapeutic strategies for osteoarthritis.
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We thank the affected individuals for participating in the study; Y. Ishii, K. Tamai, H. Ishibashi, S. Okinaga, H. Hiraoka, H. Kawaguchi, S. Saitoh, T. Kubo, Y. Takatori, H. Mototani, M. Mori, K. Yoshimura, M. Oka, M. Nakajima and K. Toyoshima for help; and A. Narita for technical assistance. This work was supported by the Japanese Millennium Project.
The authors declare no competing financial interests.
Expression of the asporin gene (ASPN) in articular cartilage from OA patients and normal (non-OA) subjects. (PDF 51 kb)
Stable overexpression of human asporin inhibits cartilage matrix accumulation in ATDC5 cells. (PDF 47 kb)
Relative inhibition of the chondrocyte differentiation marker genes AGC1 and COL2A1 by asporin D13 and D14. (PDF 39 kb)
Allelic frequency of the aspartic acid (D)-repeat polymorphism of asporin in Japanese patients with knee and hip osteoarthritis. (PDF 51 kb)
Association between seven polymorphisms in ASPN and knee osteoarthritis. (XLS 29 kb)
Clinical parameters. (XLS 29 kb)
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Kizawa, H., Kou, I., Iida, A. et al. An aspartic acid repeat polymorphism in asporin inhibits chondrogenesis and increases susceptibility to osteoarthritis. Nat Genet 37, 138–144 (2005). https://doi.org/10.1038/ng1496
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