PDF(Pubmed)
Abstract：
In response to mechanical forces and the aging process, bone in the adult skeleton is continuously remodeled by a process in which old and damaged bone is removed by bone-resorbing osteoclasts and subsequently is replaced by new bone by bone-forming cells, osteoblasts. During this essential process of bone remodeling, osteoclastic resorption is tightly coupled to osteoblastic bone formation. Bone-resorbing cells, multinuclear giant osteoclasts, derive from the monocyte/macrophage hematopoietic lineage and their differentiation is driven by distinct signaling molecules and transcription factors. Critical factors for this process are Macrophage Colony Stimulating Factor (M-CSF) and Receptor Activator Nuclear Factor-κB Ligand (RANKL). Besides their resorption activity, osteoclasts secrete coupling factors which promote recruitment of osteoblast precursors to the bone surface, regulating thus the whole process of bone remodeling. Bone morphogenetic proteins (BMPs), a family of multi-functional growth factors involved in numerous molecular and signaling pathways, have significant role in osteoblast-osteoclast communication and significantly impact bone remodeling. It is well known that BMPs help to maintain healthy bone by stimulating osteoblast mineralization, differentiation and survival. Recently, increasing evidence indicates that BMPs not only help in the anabolic part of bone remodeling process but also significantly influence bone catabolism. The deletion of the BMP receptor type 1A (BMPRIA) in osteoclasts increased osteoblastic bone formation, suggesting that BMPR1A signaling in osteoclasts regulates coupling to osteoblasts by reducing bone-formation activity during bone remodeling. The dual effect of BMPs on bone mineralization and resorption highlights the essential role of BMP signaling in bone homeostasis and they also appear to be involved in pathological processes in inflammatory disorders affecting bones and joints. Certain BMPs (BMP2 and -7) were approved for clinical use; however, increased bone resorption rather than formation were observed in clinical applications, suggesting the role BMPs have in osteoclast activation and subsequent osteolysis. Here, we summarize the current knowledge of BMP signaling in osteoclasts, its role in osteoclast resorption, bone remodeling, and osteoblast-osteoclast coupling. Furthermore, discussion of clinical application of recombinant BMP therapy is based on recent preclinical and clinical studies.
摘要：
响应机械力和老化过程，成年骨骼中的骨骼通过一个过程不断重塑，在该过程中，旧的和受损的骨骼被骨吸收的破骨细胞去除，随后被骨骼形成细胞替换为新骨，成骨细胞。在这个骨骼重建的重要过程中，破骨细胞吸收与成骨细胞骨形成紧密耦合。骨吸收细胞，多核巨大破骨细胞,来自单核细胞/巨噬细胞造血谱系，它们的分化是由不同的信号分子和转录因子驱动的。该过程的关键因素是巨噬细胞集落刺激因子(M-CSF)和受体激活剂核因子-κB配体(RANKL)。除了它们的吸收活性，破骨细胞分泌促进成骨细胞前体募集到骨表面的偶联因子，从而调节骨重建的整个过程。骨形态发生蛋白(BMPs),一个涉及许多分子和信号通路的多功能生长因子家族，在成骨细胞-破骨细胞通讯中具有重要作用，并显着影响骨重建。众所周知，BMP通过刺激成骨细胞矿化来帮助维持健康的骨骼，分化和生存。最近,越来越多的证据表明，BMP不仅有助于骨重塑过程的合成代谢部分，而且还显着影响骨分解代谢。破骨细胞中BMP受体1A型（BMPRIA）的缺失增加了成骨细胞的骨形成，提示破骨细胞中的BMPR1A信号通过降低骨重建过程中的骨形成活性来调节与成骨细胞的偶联。BMP对骨矿化和再吸收的双重作用强调了BMP信号在骨稳态中的重要作用,并且它们似乎也参与了影响骨和关节的炎性疾病的病理过程。某些BMP（BMP2和-7）被批准用于临床；然而，在临床应用中观察到骨吸收而不是形成增加，提示BMP在破骨细胞活化和随后的骨溶解中的作用。这里,我们总结了破骨细胞中BMP信号传导的最新知识，它在破骨细胞吸收中的作用，骨重塑,和成骨细胞-破骨细胞偶联。此外，讨论重组BMP治疗的临床应用是基于最近的临床前和临床研究。
