Bidwell Joseph P, Yang Jieping, Robling Alexander G
Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
J Cell Biochem. 2008 Apr 15;103(6):1671-80. doi: 10.1002/jcb.21572.
The death of osteocytes, the terminally differentiated cells of the osteoblast lineage that are embedded in bone and regulate remodeling, is significant to both normal and pathological bone resorption. Apoptotic osteocytes putatively release a clarion signal that enhances the development of the bone-resorbing osteoclasts and targets their migration to the breach in the osteocyte network. This phenomenon is thought to underlie normal repair of bone microdamage and contribute to the etiologies of inflammatory bone loss. The chromatin protein high mobility group box 1 protein (HMGB1) has been identified as an "alarmin" in other tissues. An alarmin is an endogenous molecule released by dead and dying cells that alert the innate immune system to damage and the need for tissue repair. Wang and colleagues presented evidence in a landmark 1999 study showing that released HMGB1 is a lethal mediator of sepsis. Extracellular HMGB1 is a ligand for the toll-like receptors (TLRs) and for the receptor for advanced glycation end products (RAGE) all of which amplify inflammation. Recent studies by our lab and others have shown that HMGB1 is a bone-active cytokine. It is released by apoptotic osteoblasts in vitro, including the MLO-Y4 osteocyte-like cells. Extracellular HMGB1 enhances the expression of RANKL, TNFalpha, and IL6 in osteoblastogenic bone marrow stromal cell cultures, and it is chemotactic to osteoclasts. In this prospectus we will review HMGB1 activity at the immune-bone interface and propose a role for HMGB1 as an osteocyte alarmin and mediator of normal remodeling and inflammatory bone loss.
骨细胞是成骨细胞谱系的终末分化细胞,嵌入骨组织并调节骨重塑,其死亡对正常和病理性骨吸收均具有重要意义。凋亡的骨细胞可能会释放一种信号,增强骨吸收破骨细胞的发育,并引导它们迁移至骨细胞网络的破损处。这种现象被认为是骨微损伤正常修复的基础,并与炎症性骨丢失的病因有关。染色质蛋白高迁移率族蛋白B1(HMGB1)在其他组织中已被鉴定为一种“警报素”。警报素是死亡和濒死细胞释放的内源性分子,可提醒先天免疫系统组织受到损伤并需要修复。王及其同事在1999年的一项具有里程碑意义的研究中提供了证据,表明释放的HMGB1是脓毒症的致死介质。细胞外HMGB1是Toll样受体(TLR)和晚期糖基化终产物受体(RAGE)的配体,所有这些都会放大炎症反应。我们实验室和其他研究团队最近的研究表明,HMGB1是一种骨活性细胞因子。它在体外由凋亡的成骨细胞释放,包括MLO-Y4骨细胞样细胞。细胞外HMGB1可增强成骨骨髓基质细胞培养物中RANKL、TNFα和IL-6的表达,并且对破骨细胞具有趋化作用。在本综述中,我们将回顾HMGB1在免疫-骨界面的活性,并提出HMGB1作为骨细胞警报素以及正常重塑和炎症性骨丢失介质的作用。