Nature Medicine
- 12, 665 - 670 (2006)
Published online: 7 May 2006; | doi:10.1038/nm1409
Carminerin contributes to chondrocyte calcification during endochondral ossificationTakashi Yamada1, Hirotaka Kawano1, Yu Koshizuka1, Toru Fukuda2, Kimihiro Yoshimura2, Satoru Kamekura1, Taku Saito1, Toshiyuki Ikeda1, Yosuke Kawasaki1, Yoshiaki Azuma3, Shiro Ikegawa4, Kazuto Hoshi1, Ung-il Chung1, Kozo Nakamura1, Shigeaki Kato2 & Hiroshi Kawaguchi11
Department of Sensory & Motor System Medicine, Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo, Tokyo 113-8655, Japan. 2
Institute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi 1-1-1, Bunkyo, Tokyo 113-0032, Japan. 3
Teijin Institute for Biomedical Research, Asahigaoka 4-3-2, Hino, Tokyo 191-8512, Japan. 4
Institute of Physical and Chemical Research (RIKEN), Shirokanedai, Minato, Tokyo 106-8639, Japan.
Correspondence should be addressed to Hiroshi Kawaguchi kawaguchi-ort@h.u-tokyo.ac.jp Endochondral ossification is an essential process not only for physiological skeletal development and growth, but also for pathological disorders. We recently identified a novel cartilage-specific molecule, carminerin (also known as cystatin 10 and encoded by Cst10), which is upregulated in synchrony with cartilage maturation and stimulates the later differentiation of cultured chondrocytes1. Although carminerin-deficient (Cst10-/-) mice developed and grew normally, they had a microscopic decrease in the calcification of hypertrophic chondrocytes at the growth plate. When we created experimental models of pathological endochondral ossification, we observed suppression of chondrocyte calcification during formation of osteoarthritic osteophytes, age-related ectopic ossification and healing of bone fractures in Cst10-/- mice. Cultured Cst10-/- chondrocytes showed a reduction in calcification with activation of an SRY site in the promoter of the gene encoding nucleotide pyrophosphatase phosphodiesterase 1 (NPP1, encoded by Enpp1). Functional NPP1 is required for carminerin deficiency to suppress the pathological endochondral ossifications listed above. Carminerin is the first cartilage-specific protein that contributes to chondrocyte calcification during endochondral ossification under physiological and pathological conditions through the transcriptional inhibition of NPP1.
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