BoneKEy Reports | BoneKEy Watch

Characterizing the impact of the Fam20c gene on bone development

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DOI:10.1038/bonekey.2012.148

The gene Fam20c, which is highly expressed in mammalian mineralized tissue, is mutated in the human disease Raine Syndrome (lethal osteosclerotic bone dysplasia). Previous studies have generated conflicting data on the function of the FAM20C molecule; in this study Wang et al. designed a series of experiments using Fam20c knockout mice and transgenic mice. These showed that knocking out Fam20c expression systemically, and in mineralized tissues only, resulted in hypophosphatemic rickets (softer bones) rather than the osteosclerosis (hardening of the bones) seen in Raine Syndrome.

Fam20c knockout mice showed evidence of reduced osteoblast differentiation, significant downregulation of dentin matrix protein 1 (DMP1) and osteocalcin – both osteoblast terminal differentiation markers – and much higher levels of fibroblast growth factor 23 (FGF23) in bone and serum. The authors suggest that FAM20C promotes bone formation through its impact on osteogenesis and osteoblast differentiation.

Editor's comment: This study raises the possibility that mutations in Fam20c may be another cause of hypophosphatemic rickets with elevated FGF23. However, many questions remain unanswered, such as why patients with mutations in the same gene exhibit a totally different clinical phenotype of osteosclerosis, and how Fam20c deficiency causes a suppression of Dmp1 expression that appears to be responsible for the elevation of FGF23.

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