Mosey Henry, Núñez Juan A, Goring Alice, Clarkin Claire E, Staines Katherine A, Lee Peter D, Pitsillides Andrew A, Javaheri Behzad
Skeletal Biology Group, Comparative Biomedical Sciences, The Royal Veterinary College, London, United Kingdom.
Faculty of Natural and Environmental Sciences, Biological Sciences, University of Southampton, Southampton, United Kingdom.
Front Mater. 2017 Sep 13;4:27. doi: 10.3389/fmats.2017.00027.
SCLEROSTIN () is expressed predominantly in osteocytes acting as a negative regulator of bone formation. In humans, mutations in the gene lead to skeletal overgrowth and increased bone mineral density, suggesting that SCLEROSTIN is a key regulator of bone mass. The function of SCLEROSTIN as an inhibitor of bone formation is further supported by knockout (KO) mice which display a high bone mass with elevated bone formation. Previous studies have indicated that exerts its effect on bone formation through Wnt-mediated regulation of osteoblast differentiation, proliferation, and activity. Recent studies have also suggested that SCLEROSTIN regulates angiogenesis and osteoblast-to-osteocyte transition. Despite this wealth of knowledge of the mechanisms responsible for SCLEROSTIN action, no previous studies have examined whether SCLEROSTIN regulates osteocyte and vascular configuration . Herein, we image tibiae from KO mice and their wild-type (WT) counterparts with high-resolution CT to examine whether lack of SCLEROSTIN influences the morphometric properties of lacunae and vascular canal porosity relating to osteocytes and vessels within cortical bone. Male Sost KO and WT mice ( = 6/group) were sacrificed at 12 weeks of age. Fixed tibiae were analyzed using microCT to examine cortical bone mass and architecture. Then, samples were imaged by using benchtop and synchrotron nano-computed tomography at the tibiofibular junction. Our data, consistent with previous studies show that, deficiency leads to significant enhancement of bone mass by cortical thickening and bigger cross-sectional area and we find that this occurs without modifications of tibial ellipticity, a measure of bone shape. In addition, our data show that there are no significant differences in any lacunar or vascular morphometric or geometric parameters between KO mouse tibia and WT counterparts. We, therefore, conclude that the significant increases in bone mass induced by deficiency are not accompanied by any significant modification in the density, organization, or shape of osteocyte lacunae or vascular content within the cortical bone. These data may imply that SCLEROSTIN does not modify the frequency of osteocytogenic recruitment of osteoblasts to initiate terminal osteocytic differentiation in mice.
硬化蛋白（SCLEROSTIN）主要在骨细胞中表达，作为骨形成的负调节因子。在人类中，SOST基因的突变会导致骨骼过度生长和骨矿物质密度增加，这表明硬化蛋白是骨量的关键调节因子。SOST基因敲除（KO）小鼠表现出骨量增加且骨形成升高，这进一步支持了硬化蛋白作为骨形成抑制剂的功能。先前的研究表明，SOST通过Wnt介导的对成骨细胞分化、增殖和活性的调节来发挥其对骨形成的作用。最近的研究还表明，硬化蛋白调节血管生成和成骨细胞向骨细胞的转变。尽管对硬化蛋白作用机制已有丰富的了解，但之前尚无研究探讨硬化蛋白是否调节骨细胞和血管形态。在此，我们用高分辨率CT对SOST基因敲除小鼠及其野生型（WT）对照的胫骨进行成像，以研究缺乏硬化蛋白是否会影响与皮质骨内骨细胞和血管相关的腔隙形态学特性和血管孔隙率。12周龄时处死雄性SOST基因敲除和野生型小鼠（每组n = 6）。使用显微CT分析固定的胫骨，以检查皮质骨量和结构。然后，在胫腓关节处使用台式和同步加速器纳米计算机断层扫描对样本进行成像。我们的数据与先前的研究一致，表明SOST缺乏会通过皮质增厚和更大的横截面积导致骨量显著增加，并且我们发现这种情况发生时胫骨椭圆率没有改变，胫骨椭圆率是衡量骨形状的指标。此外，我们的数据表明，SOST基因敲除小鼠胫骨与野生型对照在任何腔隙或血管形态学或几何参数上均无显著差异。因此，我们得出结论，SOST缺乏引起的骨量显著增加并未伴随着皮质骨内骨细胞腔隙的密度、组织或形状或血管含量的任何显著改变。这些数据可能意味着硬化蛋白不会改变小鼠中成骨细胞向骨细胞募集以启动终末骨细胞分化的频率。
