Postmenopausal osteoporosis is recognized to be one of the major skeleton diseases strongly associated with impaired bone formation. Previous reports have indicated that the importance of bone morphogenetic protein (BMP) signaling of osteoblast lineage in bone development via classical Smad signaling, however, its critical role in osteoporosis is still not well understood. In the current study, we aim to investigate the pathological role of BMPR1A, a key receptor of BMPs, in osteoporosis and its underlying mechanism. We first found that knockdown of BMPR1A by using Col1a1-creER in osteoblasts mitigated early bone loss of osteoporosis in mice, yet along with late bone maturation defects by reducing mineral adherence rate and bone formation rate in vivo. At the cellular level, we then observed that BMPR1A deficiency promoted the proliferation of pre-osteoblasts under osteoporotic conditions but hindered their late-stage mineralization. We finally elucidated that BMPR1A deficiency compensatorily triggered mTOR-autophagy perturbation by a higher level in early osteoporotic pre-osteoblasts thus resulting in the enhancement of transient cell proliferation but impairment of final mineralization. Taken together, this study indicated the significance of BMPR1A-mTOR/autophagy axis, as a double-edged sword, in osteoporotic bone formation and provided new cues for therapeutic strategies in osteoporosis.

中文翻译：

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ALK3(BMPR1A) 缺陷和自噬信号之间的串扰可减轻骨质疏松症中的病理性骨丢失

绝经后骨质疏松症被认为是与骨形成受损密切相关的主要骨骼疾病之一。之前的报道表明，成骨细胞谱系的骨形态发生蛋白（BMP）信号通过经典的Smad信号在骨发育中发挥着重要作用，然而，其在骨质疏松症中的关键作用仍不清楚。在本研究中，我们旨在探讨BMPs的关键受体BMPR1A在骨质疏松症中的病理作用及其潜在机制。我们首先发现，在成骨细胞中使用 Col1a1-creER 敲低 BMPR1A 可减轻小鼠骨质疏松症的早期骨丢失，但通过降低体内矿物质粘附率和骨形成率，可减轻晚期骨成熟缺陷。在细胞水平上，我们观察到 BMPR1A 缺陷促进了骨质疏松条件下前成骨细胞的增殖，但阻碍了其后期矿化。我们最终阐明，BMPR1A 缺陷补偿性地触发早期骨质疏松前成骨细胞中较高水平的 mTOR 自噬扰动，从而导致瞬时细胞增殖增强，但最终矿化受损。综上所述，本研究表明了 BMPR1A-mTOR/自噬轴作为一把双刃剑在骨质疏松骨形成中的重要性，并为骨质疏松症的治疗策略提供了新的线索。