Signaling pathways associated with Lgr6 to regulate osteogenesis

IF 3.5 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Bone Pub Date : 2024-07-19 DOI:10.1016/j.bone.2024.117207
Justin S. King , Matthew Wan , Yadav Wagley , Marta Stestiv , Ivo Kalajzic , Kurt D. Hankenson , Archana Sanjay
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Abstract

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.

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与 Lgr6 相关的调控成骨的信号通路
骨折治疗主要依靠骨骼固有的愈合能力,必要时还需要手术干预。目前,促进骨愈合的骨诱导疗法十分有限,因此,以骨骼干细胞/祖细胞(SSPCs)为靶点是一种很有前景的治疗方法。这种方法的一个限制因素是我们对支配骨骼干/祖细胞行为的分子机制了解不全面。我们最近发现,含亮氨酸丰富重复的 G 蛋白偶联受体 6(Lgr6)在 SSPCs 亚群中表达,是维持成年期骨量和骨折正常愈合所必需的。Lgr家族成员(Lgr4-6)是干细胞龛的标记,主要通过结合R-Spondin(Rspo1-4)在组织再生中发挥作用。这种相互作用通过稳定Frizzled受体促进典型Wnt(cWnt)信号的传递。有趣的是,我们的研究结果表明,Lgr6 还可能影响与 cWnt 无关的途径。值得注意的是,在 Bmp 介导的人类和鼠类细胞成骨过程中,Lgr6 的表达都得到了增强。通过生化方法、RNA 测序以及对已发表的单细胞数据进行生物信息学分析,我们发现,在 Lgr6 缺失的情况下,BMP 信号转导的元素(包括其靶基因 pSMAD 和基因本体通路)会下调。我们的发现揭示了 Bmp 通路与 Lgr6 之间的分子相互依存关系,为成骨过程提供了新的视角,也为促进骨折愈合提供了潜在靶点。
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来源期刊
Bone
Bone 医学-内分泌学与代谢
CiteScore
8.90
自引率
4.90%
发文量
264
审稿时长
30 days
期刊介绍: BONE is an interdisciplinary forum for the rapid publication of original articles and reviews on basic, translational, and clinical aspects of bone and mineral metabolism. The Journal also encourages submissions related to interactions of bone with other organ systems, including cartilage, endocrine, muscle, fat, neural, vascular, gastrointestinal, hematopoietic, and immune systems. Particular attention is placed on the application of experimental studies to clinical practice.
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