Overexpression of Fam20C in osteoblast in vivo leads to increased cortical bone formation and osteoclastic bone resorption.

Fam20C, which phosphorylates many secretory proteins with S-x-E/pS motifs, is highly expressed in bone and tooth tissues, implying that Fam20C-mediated phosphorylation is critical for regulation of these mineralized tissues. Previous studies of Fam20C-deficient mice revealed that Fam20C plays important roles in bone formation and mineralization. However, Fam20C-deficient mice develop hypophosphatemia, a systemic factor that masks the local effect of Fam20C in the bone tissue; consequently, the local role of Fam20C remains unknown. To elucidate the local function of Fam20C in bone tissue, we studied osteoblast-specific Fam20C transgenic (Fam20C-Tg) mice, which have no alteration in serum calcium and phosphate levels. Fam20C-Tg mice had more highly phosphorylated proteins in bone tissue than wild-type mice. In cortical bone of Fam20C-Tg mice, bone volume, mineralization surface (MS/BS), and mineral apposition rate (MAR) were elevated; in addition, the transgenic mice had an elevated number of vascular canals, resulting in an increased cortical porosity. Osteocyte number was elevated in the transgenics, but osteoblast number was unchanged. The microstructure of bone matrix characterized by the preferential orientation of collagen and apatite, was degraded and thus the mechanical function of bone material was deteriorated. In trabecular bone of Fam20C-Tg mice, bone volume was reduced, whereas MS/BS and MAR were unchanged. Osteoclast number was elevated and eroded surface area was non-significantly elevated with an increased serum CTX-I level, whereas osteoblast number was unchanged. These findings indicated that Fam20C overexpression in osteoblasts promotes cortical bone formation by increasing MS/BS and MAR and promoting osteocyte differentiation, but does not affect trabecular bone formation. Furthermore, Fam20C overexpression indirectly promotes osteoclastic bone resorption in cortical and trabecular bones. Our findings show that osteoblastic Fam20C-mediated phosphorylation in bone tissue regulates bone formation and resorption, and bone material quality.