Osteopenia, decreased bone formation and impaired osteoblast development in Sox4 heterozygous mice

The transcription factor Sox4 is vital for fetal development, as Sox4 (-/-) homozygotes die in utero. Sox4 mRNA is expressed in the early embryonic growth plate and is regulated by parathyroid hormone, but its function in bone modeling/remodeling is unknown. We report that Sox4(+/-) mice exhibit significantly lower bone mass ( by dual-energy X-ray absorptiometry) from an early age, and fail to obtain the peak bone mass of wild-type ( WT) animals. Microcomputed tomography ( mu CT), histomorphometry and biomechanical testing of Sox4(+/-) bones show reduced trabecular and cortical thickness, growth plate width, ultimate force and stiffness compared with WT. Bone formation rate ( BFR) in 3-month-old Sox4(+/-) mice is 64% lower than in WT. Primary calvarial osteoblasts from Sox4(+/-) mice demonstrate markedly inhibited proliferation, differentiation and mineralization. In these cultures, osterix ( Osx) and osteocalcin ( OCN) mRNA expression was reduced, whereas Runx2 mRNA was unaffected. No functional defects were found in osteoclasts. Silencing of Sox4 by siRNA in WT osteoblasts replicated the defects observed in Sox4(+/-) cells. We demonstrate inhibited formation and altered microarchitecture of bone in Sox4(+/-) mice versus WT, without apparent defects in bone resorption. Our results implicate the transcription factor Sox4 in regulation of bone formation, by acting upstream of Osx and independent of Runx2.