Mechanical Loading Synergistically Increases Trabecular Bone Volume and Improves Mechanical Properties in the Mouse when BMP Signaling Is Specifically Ablated in Osteoblasts

Bone homeostasis is affected by several factors, particularly mechanical loading and growth factor signaling pathways. There is overwhelming evidence to validate the importance of these signaling pathways, however, whether these signals work synergistically or independently to contribute to proper bone maintenance is poorly understood. Weight-bearing exercise increases mechanical load on the skeletal system and can improves bone quality. We previously reported that conditional knockout (cKO) of Bmpr1a, which encodes one of the type 1 receptors for Bone Morphogenetic Proteins (BMPs), in an osteoblast-specific manner increased trabecular bone mass by suppressing osteoclastogenesis. The cKO bones also showed increased cortical porosity, which is expected to impair bone mechanical properties. Here, we evaluated the impact of weight-bearing exercise on the cKO bone phenotype to understand interactions between mechanical loading and BMP signaling through BMPR1A. Male mice with disruption of Bmpr1a induced at 9 weeks of age, exercised 5 days per week on a motor-driven treadmill from 11 to 16 weeks of age. Trabecular bone volume in cKO tibia was further increased by exercise, whereas exercise did not affect the trabecular bone in the control genotype group. This finding was supported by decreased levels of osteoclasts in the cKO tibiae. The cortical porosity in the cKO bones showed a marginally significant decrease with exercise and approached normal levels. Exercise increased ductility and toughness in the cKO bones. Taken together, reduction in BMPR1A signaling may sensitize osteoblasts for mechanical loading to improve bone mechanical properties.

骨稳态（Bone homeostasis）受多种因素调控，其中机械负荷与生长因子信号通路的作用尤为突出。现有大量证据证实了这类信号通路的重要性，但对于这些信号究竟是协同发挥作用，还是独立参与维持正常骨代谢，目前仍缺乏清晰认知。负重运动可增加骨骼系统所承受的机械负荷，进而改善骨质量。本团队此前的研究显示，在成骨细胞特异性条件下敲除编码骨形态发生蛋白（Bone Morphogenetic Proteins, BMPs）I型受体之一的Bmpr1a基因（条件性基因敲除，cKO），可通过抑制破骨细胞生成增加骨小梁质量。该cKO模型的骨骼还表现出皮质孔隙率升高，这一改变会损害骨骼的机械性能。本研究旨在评估负重运动对该cKO骨骼表型的影响，以解析机械负荷与通过BMPR1A介导的BMP信号通路之间的相互作用。我们对9周龄时诱导Bmpr1a基因敲除的雄性小鼠，于11至16周龄期间每周进行5天的电动跑步机负重运动训练。结果显示，运动进一步提升了cKO模型小鼠胫骨的骨小梁质量，而对对照基因型组小鼠的骨小梁无显著影响。这一发现得到了cKO小鼠胫骨中破骨细胞水平降低的佐证。cKO骨骼的皮质孔隙率在运动后出现小幅且具有边际显著性的降低，趋近于正常水平。运动还提升了cKO骨骼的延展性与韧性。综上，BMPR1A信号通路的减弱或许可使成骨细胞对机械负荷更为敏感，从而改善骨骼的机械性能。