McGregor Narelle E, Walker Emma C, Chan Audrey Sm, Poulton Ingrid J, Cho Ellie H-J, Windahl Sara H, Sims Natalie A
St. Vincent's Institute of Medical Research, Fitzroy, Australia.
Centre for Muscle Research, The University of Melbourne, Melbourne, Australia.
J Bone Miner Res. 2022 Mar;37(3):547-558. doi: 10.1002/jbmr.4484. Epub 2021 Dec 16.
Cortical bone develops and changes in response to mechanical load, which is sensed by bone-embedded osteocytes. The bone formation response to load depends on STAT3 intracellular signals, which are upregulated after loading and are subject to negative feedback from Suppressor of Cytokine Signaling 3 (Socs3). Mice with Dmp1Cre-targeted knockout of Socs3 have elevated STAT3 signaling in osteocytes and display delayed cortical bone maturation characterized by impaired accrual of high-density lamellar bone. This study aimed to determine whether these mice exhibit an altered response to mechanical load. The approach used was to test both treadmill running and tibial compression in female Dmp1Cre.Socs3 mice. Treadmill running for 5 days per week from 6 to 11 weeks of age did not change cortical bone mass in control mice, but further delayed cortical bone maturation in Dmp1Cre.Socs3 mice; accrual of high-density bone was suppressed, and cortical thickness was less than in genetically-matched sedentary controls. When strain-matched anabolic tibial loading was tested, both control and Dmp1Cre.Socs3 mice exhibited a significantly greater cortical thickness and periosteal perimeter in loaded tibia compared with the contralateral non-loaded bone. At the site of greatest compressive strain, the loaded Dmp1Cre.Socs3 tibias showed a significantly greater response than controls, indicated by a greater increase in cortical thickness. This was due to a greater bone formation response on both periosteal and endocortical surfaces, including formation of abundant woven bone on the periosteum. This suggests a greater sensitivity to mechanical load in Dmp1Cre.Socs3 bone. In summary, mice with targeted SOCS3 deletion and immature cortical bone have an exaggerated response to both physiological and experimental mechanical loads. We conclude that there is an optimal level of osteocytic response to mechanical load required for cortical bone maturation and that load-induced bone formation may be increased by augmenting STAT3 signaling within osteocytes. © 2021 American Society for Bone and Mineral Research (ASBMR).
皮质骨会根据机械负荷发生发育和变化，而这种负荷由骨内的骨细胞感知。骨对负荷的形成反应取决于信号转导和转录激活因子3（STAT3）的细胞内信号，该信号在负荷后上调，并受到细胞因子信号转导抑制因子3（Socs3）的负反馈调节。通过Dmp1Cre靶向敲除Socs3的小鼠，其骨细胞中的STAT3信号增强，并表现出皮质骨成熟延迟，特征为高密度板层骨的积累受损。本研究旨在确定这些小鼠对机械负荷的反应是否改变。采用的方法是对雌性Dmp1Cre.Socs3小鼠进行跑步机跑步和胫骨压缩测试。6至11周龄的对照小鼠每周进行5天的跑步机跑步，皮质骨量未发生变化，但Dmp1Cre.Socs3小鼠的皮质骨成熟进一步延迟；高密度骨的积累受到抑制，皮质厚度小于基因匹配的久坐对照小鼠。当测试应变匹配的合成代谢性胫骨负荷时，与对侧未加载的骨骼相比，对照小鼠和Dmp1Cre.Socs3小鼠加载的胫骨均表现出显著更大的皮质厚度和骨膜周长。在最大压缩应变部位，加载的Dmp1Cre.Socs3胫骨显示出比对照小鼠更大的反应，表现为皮质厚度增加更大。这是由于骨膜和骨内膜表面的骨形成反应更大，包括骨膜上形成大量编织骨。这表明Dmp1Cre.Socs3骨对机械负荷更敏感。总之，靶向缺失SOCS3且皮质骨未成熟的小鼠对生理和实验性机械负荷均有过度反应。我们得出结论，皮质骨成熟需要骨细胞对机械负荷有最佳水平的反应，并且通过增强骨细胞内的STAT3信号，负荷诱导的骨形成可能会增加。© 2021美国骨与矿物质研究学会（ASBMR）
