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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This study was supported by a Grant-in-aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science, and Technology (#14370454), and by the Investigation Committee on the Ossification of Spinal Ligaments, Japanese Ministry of Public Health and Welfare.
The authors declare no competing financial interests.
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Radiological and histological findings of age-related ectopic ossification. (PDF 469 kb)
Ex vivo cultures of growth plate chondrocytes and calvarial osteoblasts. (PDF 989 kb)
Effects of putative cytokines on the carminerin signaling to inhibit NPP1. (PDF 190 kb)
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Yamada, T., Kawano, H., Koshizuka, Y. et al. Carminerin contributes to chondrocyte calcification during endochondral ossification. Nat Med 12, 665–670 (2006). https://doi.org/10.1038/nm1409
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