高糖对骨代谢信号通路的影响研究进展

Research progress in the effects of high glucose on signaling pathways in bone metabolism

糖尿病是一种患病率极高的慢性代谢紊乱性疾病,可以引起多个系统和脏器的损害。在肌肉骨骼系统,可导致骨质疏松、骨折愈合延迟或不愈合,影响患者的预后和生活质量,并造成巨大的医疗和经济负担。引起这些骨骼并发症的主要原因是骨形成和骨吸收的平衡被打破,使骨代谢发生紊乱。糖尿病患者出现骨代谢紊乱的机制十分复杂,涉及高血糖、晚期糖基化终末产物累积、胰岛素水平、炎症因子、氧化应激、生长因子、脂肪细胞因子和降糖药物等诸多因素,其中高血糖作为糖尿病的重要特征对骨代谢的影响最为明显。高糖影响骨代谢主要是通过作用于复杂的信号转导通路实现的。最新的研究表明,PI3K/Akt通路、cAMP/PKA通路、Wnt通路、MARK通路、AMPK/mTOR/ULK1通路、BMP通路、EphrinB2/EphB4通路、PPARγ通路和NF-κB通路等均可参与高糖对骨代谢的调节。这些信号通路对调控骨髓间质干细胞、成骨细胞和破骨细胞等细胞的生长、增殖、分化、凋亡和衰老具有重要意义,成为当前的研究热点。虽然相关研究已取得一定的进展,但仍存在很大的局限性,如研究干扰因素众多、体内研究较少,使研究结果还需要进一步证实。对高糖影响骨代谢信号通路的文献进行综述,有利于进一步了解高糖调控骨代谢的分子机制,为糖尿病骨病的防治提供理论基础和思路。

Diabetes mellitus (DM), a highly prevalent chronic metabolic disorder, can damage multiple organ systems. For instance, in the skeletal system, DM can lead to osteoporosis, delayed fracture healing or nonunion of fractures, which not only affects the prognosis of bone diseases and quality of life but also leads to huge medical and economic burden. The main reason of these skeletal complications is the disruption of the balance between bone formation and bone resorption, which leads to the disorders of bone metabolism. The mechanism of bone metabolism disorders in DM patients is determined by many biological factors, including high glucose (HG), oxidative stress, accumulation of advanced glycation end products (AGEs), insulin levels, inflammatory factors, growth factors, adipocytokines and hypoglycemic agents. Furthermore, as an important feature of DM, HG has obvious effects on bone metabolism mainly by acting on signal transduction pathways, including PI3K/Akt pathway, cAMP/PKA pathway, Wnt pathway, MARK pathway, AMPK/mTOR/ULK1 pathway, BMP pathway, EphrinB2/EphB4 pathway, PPARγ pathway and NF-κB pathway. The above mentioned signal pathways regulate the proliferation, differentiation, apoptosis and aging of cells, such as bone marrow mesenchymal stem cells (BMSCs), osteoblasts and osteoclasts. These research areas have become the current hotspot for investigation. Although some studies has been conducted in these research areas, several limitations are still exist especially in vivo study. Thus, further studies are required. The present article reviews the effects of HG on bone metabolism signaling pathways. The purpose of this review is conducive to further understand the molecular mechanism of bone metabolism regulated by HG, and to provide theoretical basis and orientations for prevention and treatment of diabetic bone diseases.