Wu Jianhui, Ren Bowen, Shi Fuli, Hua Ping, Lin Hui
Jiangxi Medical School, Nanchang University, Nanchang, Jiangx, China.
Nanchang Joint Programme, Queen Mary University of London, London, UK.
J Cell Biochem. 2019 Aug;120(8):12108-12122. doi: 10.1002/jcb.28710. Epub 2019 Apr 15.
Heterotopic ossification (HO) refers to the pathological formation of ectopic bone in soft tissues, it occurs following severe trauma or in patients with a rare genetic disorder known as fibrodysplasia ossificans progressiva. The pathological process of HO formation is a two-step mechanism: inflammation and destruction of connective tissues, followed by bone formation. The latter is further subdivided into three stages: fibroproliferation/angiogenesis, chondrogenesis, and osteogenesis. Currently, therapeutic options for HO are limited. New potential therapeutics will most likely arise from a more detailed understanding of the signaling pathways implicated in each stage of ectopic bone formation and molecular targets that may be effective at both the early and late stages of HO. Bone morphogenetic protein (BMP) signaling is believed to play a key role in the overall HO process. Recently, the mammalian target of rapamycin (mTOR) signaling pathway has received attention as a critical pathway for chondrogenesis, osteogenesis, and HO. Inhibition of mTOR signaling has been shown to block trauma-induced and genetic HO. Intriguingly, recent studies have revealed crosstalk between mTOR and BMP signaling. Moreover, mTOR has emerged as a factor involved in the early hypoxic and inflammatory stages of HO. We will summarize the current knowledge of the roles of mTOR and BMP signaling in HO, with a particular focus on the crosstalk between mTOR and BMP signaling. We also discuss the activation of AMP activated protein kinase (AMPK) by the most widely used drug for type 2 diabetes, metformin, which exerts a dual negative regulatory effect on mTOR and BMP signaling, suggesting that metformin is a promising drug treatment for HO. The discovery of an mTOR-BMP signaling network may be a potential molecular mechanism of HO and may represent a novel therapeutic target for the pharmacological control of HO.
异位骨化（HO）是指软组织中异位骨的病理性形成，它发生在严重创伤后或患有罕见遗传性疾病进行性骨化性纤维发育不良的患者中。HO形成的病理过程是一个两步机制：结缔组织的炎症和破坏，随后是骨形成。后者进一步细分为三个阶段：纤维增殖/血管生成、软骨生成和成骨。目前，HO的治疗选择有限。新的潜在治疗方法很可能源于对异位骨形成各阶段所涉及的信号通路以及可能在HO早期和晚期均有效的分子靶点的更详细了解。骨形态发生蛋白（BMP）信号通路被认为在整个HO过程中起关键作用。最近，雷帕霉素哺乳动物靶点（mTOR）信号通路作为软骨生成、成骨和HO的关键通路受到关注。mTOR信号通路的抑制已被证明可阻断创伤诱导的和遗传性HO。有趣的是，最近的研究揭示了mTOR与BMP信号通路之间的相互作用。此外，mTOR已成为参与HO早期缺氧和炎症阶段的一个因素。我们将总结目前关于mTOR和BMP信号通路在HO中的作用的知识，特别关注mTOR与BMP信号通路之间的相互作用。我们还讨论了2型糖尿病最常用药物二甲双胍对AMP激活蛋白激酶（AMPK）的激活，其对mTOR和BMP信号通路具有双重负调节作用，这表明二甲双胍是一种有前景的HO药物治疗方法。mTOR - BMP信号网络的发现可能是HO的潜在分子机制，并且可能代表HO药物控制的新治疗靶点。
