骨折管理很大程度上依赖于骨的固有愈合能力,必要时,手术干预。目前,促进愈合的骨诱导疗法有限,使靶向骨骼干/祖细胞(SSPC)成为治疗发展的有希望的途径。这种方法的一个限制因素是我们对控制SSPCs行为的分子机制的不完全理解。我们最近发现富含亮氨酸的重复序列的G蛋白偶联受体6(Lgr6)在SSPCs的亚群中表达,并且是维持成年期间的骨体积和适当的骨折愈合所必需的。Lgr家族成员(Lgr4-6)是干细胞生态位的标志物,主要通过结合R-Sondin(Rspol-4)在组织再生中发挥作用。这种相互作用通过稳定Frizzled受体促进经典Wnt(cWnt)信号传导。有趣的是,我们的研究结果表明,Lgr6也可能影响cWnt非依赖性途径。值得注意的是,在人和鼠细胞的Bmp介导的成骨过程中,Lgr6的表达均得到增强。使用生化方法,RNA测序,和已发表的单细胞数据的生物信息学分析,我们发现BMP信号的元素,包括它的目标基因,pSMAD,和基因本体论途径,在没有Lgr6的情况下下调。我们的发现揭示了Bmp途径和Lgr6之间的分子相互依赖性,为骨形成和增强骨折愈合的潜在目标提供了新的见解。
Fracture management largely relies on the bone\'s inherent healing capabilities and, when necessary, surgical intervention. Currently, there are limited osteoinductive therapies to promote healing, making targeting skeletal stem/progenitor cells (SSPCs) a promising avenue for therapeutic development. A limiting factor for this approach is our incomplete understanding of the molecular mechanisms governing SSPCs\' behavior. We have recently identified that the Leucine-rich repeat-containing G-protein coupled receptor 6 (Lgr6) is expressed in sub-populations of SSPCs, and is required for maintaining bone volume during adulthood and for proper fracture healing. Lgr family members (Lgr4-6) are markers of stem cell niches and play a role in tissue regeneration primarily by binding R-Spondin (Rspo1-4). This interaction promotes canonical Wnt (cWnt) signaling by stabilizing Frizzled receptors. Interestingly, our findings here indicate that Lgr6 may also influence cWnt-independent pathways. Remarkably, Lgr6 expression was enhanced during
Bmp-mediated osteogenesis of both human and murine cells. Using biochemical approaches, RNA sequencing, and bioinformatic analysis of published single-cell data, we found that elements of
BMP signaling, including its target gene, pSMAD, and gene ontology pathways, are downregulated in the absence of Lgr6. Our findings uncover a molecular interdependency between the
Bmp pathway and Lgr6, offering new insights into osteogenesis and potential targets for enhancing fracture healing.