Osteopenia, decreased bone formation and impaired osteoblast development inSox4heterozygous mice

Abstract

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 (μCT), 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.

The Transcription Factor Protein Sox11 Enhances Early Osteoblast Differentiation by Facilitating Proliferation and the Survival of Mesenchymal and Osteoblast Progenitors

“…However, during osteoblast differentiation, Sox4 was remarkably increased, whereas the levels of Sox11 were decreased (data not shown). Our findings also supported a previous report on the involvement of Sox4 in osteoblast differentiation (25). In addition, the co-expression patterns of Sox4, Sox11, and Sox12 in mesenchymal and neuronal tissues were previously reported (20).…”

Transcription Factors SOX4 and SOX11 Function Redundantly to Regulate the Development of Mouse Retinal Ganglion Cells

“…Abrogation of Sox4/11 in vivo suppresses the differentiation of adult neuron stem cells and does not affect the apoptosis (20). In addition, knocking down of Sox4 is reported to damage proliferation of osteoblasts in vitro (37). The proliferation of pancreatic islet cells is also impaired in Sox4-null pancreas cultured in vitro but Sox4 deficiency has no impact on cell survival of insulin producing cells (38).…”

TXNIP is highly regulated in bone biopsies from patients with endogenous Cushing's syndrome and related to bone turnover

“…Alkaline phosphatase (ALP) staining was determined using Sigma kit 104-LS, as previously described (Sigma) (18).…”