Nissen-Meyer Lise Sofie Haug, Jemtland Rune, Gautvik Vigdis T, Pedersen Mona E, Paro Rita, Fortunati Dario, Pierroz Dominique D, Stadelmann Vincent A, Reppe Sjur, Reinholt Finn P, Del Fattore Andrea, Rucci Nadia, Teti Anna, Ferrari Serge, Gautvik Kaare M
Department of Biochemistry, Institute of Basic Medical Sciences, University of Oslo, N-0317 Oslo, Norway.
J Cell Sci. 2007 Aug 15;120(Pt 16):2785-95. doi: 10.1242/jcs.003855. Epub 2007 Jul 24.
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 (muCT), 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.
转录因子Sox4对胎儿发育至关重要，因为Sox4(-/-)纯合子在子宫内死亡。Sox4 mRNA在早期胚胎生长板中表达，并受甲状旁腺激素调节，但其在骨塑形/重塑中的功能尚不清楚。我们报告称，Sox4(+/-)小鼠从幼年起骨量就显著降低（通过双能X线吸收法测定），且未能达到野生型（WT）动物的峰值骨量。对Sox4(+/-)骨骼进行的微型计算机断层扫描（μCT）、组织形态计量学和生物力学测试显示，与WT相比，其小梁和皮质厚度、生长板宽度、极限力和刚度均降低。3个月大的Sox4(+/-)小鼠的骨形成率（BFR）比WT低64%。来自Sox4(+/-)小鼠的原代颅骨成骨细胞表现出明显的增殖、分化和矿化抑制。在这些培养物中，osterix（Osx）和骨钙素（OCN）mRNA表达降低，而Runx2 mRNA不受影响。在破骨细胞中未发现功能缺陷。在WT成骨细胞中通过siRNA沉默Sox4可重现Sox4(+/-)细胞中观察到的缺陷。我们证明，与WT相比，Sox4(+/-)小鼠的骨形成受到抑制且微观结构改变，而骨吸收无明显缺陷。我们的结果表明，转录因子Sox4通过在Osx上游起作用且独立于Runx2来调节骨形成。
