Targeting Bone Cells During Sexual Maturation Reveals Sexually Dimorphic Regulation of Endochondral Ossification.
Targeting Bone Cells During Sexual Maturation Reveals Sexually Dimorphic Regulation of Endochondral Ossification.
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作者：
Fairfield H;Costa S;DeMambro V;Schott C;Martins JDS;Ferron M;Vary C;Reagan MR
在软骨内骨化中，成软骨细胞嵌入其基质中并成为软骨细胞，软骨细胞是继续增殖的成熟细胞，最终变得肥大。肥大的软骨细胞产生软骨，然后在通过成骨细胞进行骨基质置换之前被破骨细胞再吸收。虽然性二态性骨表型的特点，具体的调制生长板在性成熟的一个关键窗口尚未进行评估。在这里，我们报告了性成熟过程中体内表达骨钙素-（OCN-）的细胞的特异性耗竭导致男性和女性骨表型的二态性。在6至8周龄时，用白喉毒素（DT）处理OCN-Cre;iDTR（诱导型白喉毒素受体表达）小鼠2周以消耗OCN+细胞。在研究结束时，收集长骨用于μCT和组织形态计量学，并收集血清用于蛋白质组学和脂质组学分析。小鼠中OCN+细胞的消融导致治疗2周后体重减轻的一致趋势。正如预期，雌性动物对OCN+细胞消融治疗的响应表现出骨骼参数降低。然而，雄性动物中的OCN+细胞消融仅显示肥大软骨细胞扩张、生长板增宽和股骨远端异常“杵状”解剖结构。DT处理后，两种性别的小鼠也进行了代谢笼分析，其中两种性别的小鼠均表现出能量消耗降低。我们的结论是，在纵向生长过程中，倾斜的软骨内骨形成对体重和能量消耗有深远的影响，对发育中的骨有性别特异性影响。版权所有2020作者。JBMR Plus由Wiley Periodicals LLC代表美国骨与矿物质研究学会出版。
In endochondral ossification, chondroblasts become embedded in their matrix and become chondrocytes, which are mature cells that continue to proliferate, eventually becoming hypertrophic. Hypertrophic chondrocytes produce cartilage that is then resorbed by osteoclasts prior to bone matrix replacement via osteoblasts. Although sexually dimorphic bone phenotypes have long been characterized, specific modulation of the growth plate during a critical window in sexual maturation has not been evaluated. Here we report that specific depletion of osteocalcin‐ (OCN‐) expressing cells in vivo during sexual maturation leads to dimorphic bone phenotypes in males and females. At 6 to 8 weeks of age, OCN‐Cre;iDTR (inducible diphtheria toxin receptor‐expressing) mice were treated with diphtheria toxin (DT) for 2 weeks to deplete OCN+ cells. At the end of the study, long bones were collected for μCT and histomorphometry, and serum was collected for proteomic and lipidomic analyses. Ablation of OCN+ cells in mice leads to consistent trends for weight loss after 2 weeks of treatment. Females exhibited decreased skeletal parameters in response to OCN+ cell ablation treatment, as expected. However, OCN+ cell ablation in males uniquely displayed an expansion of hypertrophic chondrocytes, a widening of the growth plate, and an abnormal “clubbing” anatomy of the distal femur. Following DT treatment, mice from both sexes also underwent metabolic cage analysis, in which both sexes exhibited decreased energy expenditure. We conclude that skewing endochondral bone formation during longitudinal growth has a profound effect on body weight and energy expenditure with sex‐specific effects on developing bone. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.