MECHANICAL FORCES, OSTEOCYTES VAIBILITY, BONE STRENGTH

骨细胞检测机械适应和微损伤修复的需要，并向成骨细胞或 破骨细胞，导致骨量增加或减少。尽管骨细胞寿命很长，但它们会发生凋亡，并具有生存能力。 通过依赖和不依赖于骨密度变化的机制来提高骨强度。 在前一次供资期间，发现与激素和药物刺激类似， 机械力调节骨细胞的寿命。因此，体外机械刺激可阻止骨细胞的凋亡 通过整合素/Src/ERK途径，需要小窝的完整性和配体无关的功能 雌激素受体(ER)。相反，体内机械力的减少会增加骨细胞的凋亡，而这 事件在时间上先于破骨细胞介导的吸收，并在空间上与破骨细胞介导的吸收和随后的 矿物质和体力的丧失。研究还发现，在衰老过程中，骨骼强度会先下降，然后再下降 骨密度增加，骨细胞凋亡率增加。在此基础上，提出了 机械刺激触发ERK依赖的信号，通过组装在 小窝，由整合素和信号分子组成，包括内质网。相反，减少了 机械力？？随着年龄增长而减少的体力活动？？消除了维持骨细胞的信号。 生存能力，从而导致细胞凋亡。濒临死亡的骨细胞继而招募破骨细胞到附近。两者都有 机制，破坏骨细胞网络的完整性和增加破骨细胞性骨吸收， 导致与年龄相关的骨强度和骨量下降。为了验证这些假设，在目标1中将 内质网和小窝蛋白-1在ERK介导的机械性诱导的抗细胞凋亡中的作用 刺激；以及其他生存信号通路是否协同作用来控制骨细胞死亡。在目标2中，它 将在体内确定机械诱导的生存信号是否被卸载和在 衰老，并确定了卸载或衰老是否诱导破骨细胞介导的骨吸收和丢失以及 通过1)结构性激活OG2中的ERK通路来抑制骨细胞的凋亡，从而改善强度 MEK-SP小鼠，2)DMP1-Bcl2小鼠过表达抗凋亡蛋白，3)A 独一无二的双膦酸盐，可抑制骨细胞的凋亡，而不影响破骨细胞。在《目标3》中，它将是 确定诱导骨细胞凋亡是否足以触发破骨细胞募集，以及 破骨细胞对细胞凋亡的反应动力学随着年龄的增长而改变。这些研究将 推进我们对机械力的深刻作用的机械基础的理解，或缺乏机械力， 在骨骼健康和疾病中的作用，并将确定骨细胞凋亡对骨丢失的贡献 随着年龄的增长而产生的力量。我们期待这项工作将为骨的治疗提供新的途径。 在体力活动减少的情况下的脆弱，例如在老年人或在临时制动期间 卧床休息、太空飞行和运动性瘫痪。

Osteocytes detect the need for mechanical adaptation and microdamage repair and signal to osteoblasts or osteoclasts, leading to bone gain or loss. Although long-lived, osteocytes undergo apoptosis, and their viability contributes to bone strength by mechanisms dependent and independent of changes in bone mineral density. During the preceding funding period, it was found that, similar to hormonal and pharmacological stimuli, mechanical forces regulate osteocyte lifespan. Thus, mechanical stimulation in vitro prevents osteocyte apoptosis via an integrin/Src/ERK pathway that requires the integrity of caveolae and a ligand-independent function of the estrogen receptor (ER). Conversely, reduced mechanical forces in vivo increase osteocyte apoptosis, and this event temporally precedes, and is spatially associated with, osteoclast-mediated resorption and the subsequent loss of mineral and strength. It was also found that during aging bone strength decreases before a reduction in bone mineral density, and osteocyte apoptosis increases. Based on this knowledge, it is proposed that mechanical stimuli trigger ERK-dependent signals that sustain osteocyte survival via a signalsome assembled in caveolae and composed of integrins and signaling molecules, including the ERs. Conversely, diminished mechanical forces?from reduced physical activity with age?eliminate the signals that maintain osteocyte viability, thereby leading to apoptosis. Dying osteocytes in turn recruit osteoclasts to the vicinity. Both mechanisms, disruption of the integrity of the osteocyte network and increased osteoclastic bone resorption, contribute to the age-related decline in bone strength and mass. To validate these hypotheses, in Aim 1 will be defined in vitro the role of the ER and caveolin-1 in ERK-mediated anti-apoptosis induced by mechanical stimulation; and whether other survival signaling pathways act in concert to control osteocyte death. In Aim 2, it will be determined in vivo whether mechanically induced survival signaling is disrupted by unloading and during aging, and established whether unloading- or aging-induced osteoclast-mediated resorption and loss of bone and strength are ameliorated by inhibiting osteocyte apoptosis by 1) constitutively activating the ERK pathway in OG2- MEK-SP mice, 2) overexpressing the anti-apoptotic protein Bcl-2 in DMP1-Bcl2 mice, and 3) treating with a unique bisphosphonate that inhibits osteocyte apoptosis without affecting osteoclasts. In Aim 3, it will be established whether induction of osteocyte apoptosis is sufficient to trigger osteoclast recruitment and whether the kinetics of the osteoclastogenic response to osteocyte apoptosis are altered with aging. These studies will advance our understanding of the mechanistic basis for the profound role of mechanical forces, or lack of thereof, in skeletal health and disease, and will establish the contribution of osteocyte apoptosis to the loss of bone strength that ensues with aging. We expect that this work will provide new avenues for the treatment of bone fragility in conditions of reduced physical activity, such as in the elderly or during the temporary immobilization of bed rest, space flight, and motor paralysis.