Erlandsson Malin C, Bian Li, Jonsson Ing-Marie, Andersson Karin M, Bokarewa Maria I
Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, University of Göteborg, S-41346 Göteborg, Sweden.
Mol Endocrinol. 2013 Aug;27(8):1311-21. doi: 10.1210/me.2012-1398. Epub 2013 Jun 24.
S100A4 is a Ca-binding protein participating in regulation of cell growth, survival, and motility. Here we studied the role of S100A4 protein in sex hormone-regulated bone formation. Bone mineral density in the trabecular and cortical compartments was evaluated in female S100A4 knockout (KO), in matched wild-type (WT) counterparts, and in WT mice treated with lentiviral small hairpin RNA construct inhibiting the S100A4 gene transcription or with a nontargeting construct, by peripheral quantitative computed tomography. The effect of sex hormones on bone was measured 5 weeks after ovariectomy (OVX) and/or dehydroepiadrosterone treatment. S100A4KO had an excessive trabecular and cortical bone formation compared with the age- and sex-matched WT mice. S100A4KO had an increased periosteal circumference (P = .001), cortical thickness (P = .056), and cortical area (P = .003), which predicted 20% higher bone strength in S100A4KO (P = .013). WT mice treated with small hairpin RNA-S100A4 showed an increase of the cortical bone parameters in a fashion identical with S100A4KO mice, indicating the key role of S100A4 in the changed bone formation. S100A4KO mice had higher serum levels of osteocalcin and a higher number of osteocalcin-positive osteoblasts under the periosteum. OVX-S100A4 resulted in the loss of the cortical bone supported by high CTX-I levels, whereas no such changes were observed in OVX-WT mice. S100A4KO mice resisted the dehydroepiadrosterone -induced bone formation observed in the WT counterparts. Our study indicates that S100A4 is a regulator of bone formation, which inhibits bone excess in the estrogen-sufficient mice and prevents the cortical bone loss in the estrogen-deprived mice.
S100A4是一种参与细胞生长、存活和运动调节的钙结合蛋白。在此，我们研究了S100A4蛋白在性激素调节骨形成中的作用。通过外周定量计算机断层扫描，对雌性S100A4基因敲除（KO）小鼠、匹配的野生型（WT）对照小鼠，以及用抑制S100A4基因转录的慢病毒短发夹RNA构建体或非靶向构建体处理的WT小鼠的小梁和皮质骨区域的骨密度进行了评估。在卵巢切除术（OVX）和/或脱氢表雄酮治疗5周后，测量性激素对骨的影响。与年龄和性别匹配的WT小鼠相比，S100A4基因敲除小鼠的小梁和皮质骨形成过多。S100A4基因敲除小鼠的骨膜周长增加（P = 0.001）、皮质厚度增加（P = 0.056）和皮质面积增加（P = 0.003），这预示着S100A4基因敲除小鼠的骨强度高20%（P = 0.013）。用短发夹RNA-S100A4处理的WT小鼠的皮质骨参数以与S100A4基因敲除小鼠相同的方式增加，表明S100A4在改变的骨形成中起关键作用。S100A4基因敲除小鼠的血清骨钙素水平较高，骨膜下骨钙素阳性成骨细胞数量较多。OVX-S100A4导致高CTX-I水平支持的皮质骨丢失，而在OVX-WT小鼠中未观察到此类变化。S100A4基因敲除小鼠抵抗了在野生型对照小鼠中观察到的脱氢表雄酮诱导的骨形成。我们的研究表明，S100A4是骨形成的调节因子，它在雌激素充足的小鼠中抑制骨过度生长，并在雌激素缺乏的小鼠中防止皮质骨丢失。
