Osteoblast-Specific Overexpression of Human WNT16 Increases Both Cortical and Trabecular Bone Mass and Structure in Mice
Osteoblast-Specific Overexpression of Human WNT16 Increases Both Cortical and Trabecular Bone Mass and Structure in Mice
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DOI：
10.1210/en.2015-1281
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发表时间：
2016-02-01
期刊：
影响因子：
4.8
通讯作者：
Econs, Michael J.
中科院分区：
文献类型：
--
作者：
Alam, Imranul;Alkhouli, Mohammed;Econs, Michael J.
以前的全基因组关联研究已经确定了与骨矿物质密度（BMD）和骨折风险相关的基因的常见变异。最近，我们在无翅型乳腺肿瘤病毒整合位点（WNT）16上发现了与绝经前妇女峰值BMD相关的单核苷酸多态性（SNPs）。为了进一步确定WNT 16在骨量调节中的作用，我们创建了在成骨细胞中过表达人WNT 16的转基因（TG）小鼠。我们比较了TG和野生型（WT）小鼠的骨表型、血清生化、基因表达和动态骨组织形态计量学。与WT小鼠相比，WNT 16-TG小鼠在6周龄和12周龄时，雄性和雌性的全身区域BMD和骨矿物质含量（BMC）均显著较高。股骨远端骨小梁的计算机断层扫描分析显示，与WT同窝小鼠相比，两种性别的TG小鼠的骨体积/组织体积（BV/TV）分别高3倍（雄性）和14倍（雌性），骨小梁数量和骨小梁厚度显著增加，但骨小梁分离较低。股骨中段的皮质骨在两种性别的TG小鼠中也显示出显著的股骨面积/总面积和皮质厚度。血清生化分析显示，与WT小鼠相比，雄性TG小鼠具有较高的血清碱性磷酸酶、骨钙素、骨保护素（OPG）、OPG与NF-κ B配体（肿瘤坏死家族配体超家族，第11号; RANKL）受体活化剂的比率。此外，与WT同窝出生的雄性和雌性小鼠相比，在TG小鼠中观察到较低的羧基末端胶原交联（CTX）与抗酒石酸酸性磷酸酶5亚型B（TRAPc 5 B）的比率。组织形态学数据表明，雄性和雌性TG小鼠的皮质和骨小梁矿化表面/骨表面和骨形成率均显著高于性别匹配的WT小鼠。基因表达分析表明，与WT同窝出生小鼠相比，TG小鼠骨组织中Alp、OC、Opg和Opg与Rankl的比率的表达更高。我们的数据表明，WNT 16是至关重要的积极调节皮质和骨小梁的质量和结构，这种分子可能是针对治疗干预，以治疗骨质疏松症。
Previous genome-wide association studies have identified common variants in genes associated with bone mineral density (BMD) and risk of fracture. Recently, we identified single nucleotide polymorphisms (SNPs) in Wingless-typemousemammarytumor virus integration site (WNT) 16 that were associated with peak BMD in premenopausal women. To further identify the role of Wnt16 in bone mass regulation, we created transgenic (TG) mice overexpressing human WNT16 in osteoblasts. We compared bone phenotypes, serum biochemistry, gene expression, and dynamic bone histomorphometry between TG and wild-type (WT) mice. Compared with WT mice, WNT16-TG mice exhibited significantly higher whole-body areal BMD and bone mineral content (BMC) at 6 and 12 weeks of age in both male and female. Microcomputer tomography analysis of trabecular bone at distal femur revealed 3-fold (male) and 14-fold (female) higher bone volume/tissue volume (BV/TV), and significantly higher trabecular number and trabecular thickness but lower trabecular separation in TG mice compared with WT littermates in both sexes. The cortical bone at femur midshaft also displayed significantly greaterbonearea/total area and cortical thickness in the TG mice in both sexes. Serum biochemistry analysis showed that male TG mice had higher serum alkaline phosphatase, osteocalcin, osteoprotegerin (OPG), OPG to receptor activator of NF-kappa B ligand (tumor necrosis family ligand superfamily, number 11; RANKL) ratio as compared with WT mice. Also, lower carboxy-terminal collagen cross-link (CTX) to tartrate-resistant acid phosphatase 5, isoform b (TRAPc5b) ratio was observed in TG mice compared with WT littermates in both male and female. Histomorphometry data demonstrated that both male and female TG mice had significantly higher cortical and trabecular mineralizing surface/bone surface and bone formation rate compared with sex-matched WT mice. Gene expression analysis demonstrated higher expression of Alp, OC, Opg, and Opg to Rankl ratio in bone tissue in the TG mice compared with WT littermates. Our data indicate that WNT16 is critical for positive regulation of both cortical and trabecular bone mass and structure and that this molecule might be targeted for therapeutic interventions to treat osteoporosis.