Mapping RANKL- and OPG-expressing cells in bone tissue: the bone surface cells as activators of osteoclastogenesis and promoters of the denosumab rebound effect

IF 14.3 1区 医学 Q1 CELL & TISSUE ENGINEERING Bone Research Pub Date : 2024-10-18 DOI:10.1038/s41413-024-00362-4
Bilal M. El-Masri, Christina M. Andreasen, Kaja S. Laursen, Viktoria B. Kofod, Xenia G. Dahl, Malene H. Nielsen, Jesper S. Thomsen, Annemarie Brüel, Mads S. Sørensen, Lars J. Hansen, Albert S. Kim, Victoria E. Taylor, Caitlyn Massarotti, Michelle M. McDonald, Xiaomeng You, Julia F. Charles, Jean-Marie Delaisse, Thomas L. Andersen
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Abstract

Denosumab is a monoclonal anti-RANKL antibody that inhibits bone resorption, increases bone mass, and reduces fracture risk. Denosumab discontinuation causes an extensive wave of rebound resorption, but the cellular mechanisms remain poorly characterized. We utilized in situ hybridization (ISH) as a direct approach to identify the cells that activate osteoclastogenesis through the RANKL/OPG pathway. ISH was performed across species, skeletal sites, and following recombinant OPG (OPG:Fc) and parathyroid hormone 1–34 (PTH) treatment of mice. OPG:Fc treatment in mice induced an increased expression of RANKL mRNA mainly in trabecular, but not endocortical bone surface cells. Additionally, a decreased expression of OPG mRNA was detected in bone surface cells and osteocytes of both compartments. A similar but more pronounced effect on RANKL and OPG expression was seen one hour after PTH treatment. These findings suggest that bone surface cells and osteocytes conjointly regulate the activation of osteoclastogenesis, and that OPG:Fc treatment induces a local accumulation of osteoclastogenic activation sites, ready to recruit and activate osteoclasts upon treatment discontinuation. Analysis of publicly available single-cell RNA sequencing (scRNAseq) data from murine bone marrow stromal cells revealed that Tnfsf11+ cells expressed high levels of Mmp13, Limch1, and Wif1, confirming their osteoprogenitor status. ISH confirmed co-expression of Mmp13 and Tnfsf11 in bone surface cells of both vehicle- and OPG:Fc-treated mice. Under physiological conditions of human/mouse bone, RANKL is expressed mainly by osteoprogenitors proximate to the osteoclasts, while OPG is expressed mainly by osteocytes and bone-forming osteoblasts.

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绘制骨组织中的 RANKL 和 OPG 表达细胞图:骨表面细胞是破骨细胞生成的激活剂和地诺单抗反弹效应的促进剂
地诺单抗是一种单克隆抗 RANKL 抗体,可抑制骨吸收、增加骨量并降低骨折风险。停用地诺单抗会引起广泛的骨吸收反弹,但其细胞机制仍鲜为人知。我们利用原位杂交(ISH)作为一种直接方法来识别通过 RANKL/OPG 通路激活破骨细胞生成的细胞。我们对不同物种、不同骨骼部位以及重组 OPG(OPG:Fc)和甲状旁腺激素 1-34 (PTH) 处理后的小鼠进行了 ISH 研究。小鼠经 OPG:Fc 处理后,RANKL mRNA 主要在骨小梁而非皮质内骨表面细胞中的表达增加。此外,在骨表面细胞和两个区段的骨细胞中均检测到 OPG mRNA 表达减少。PTH 处理一小时后,对 RANKL 和 OPG 表达的影响类似但更明显。这些研究结果表明,骨表面细胞和骨细胞共同调控破骨细胞生成的激活,OPG:Fc 处理会诱导破骨细胞生成激活点的局部聚集,并在处理停止后招募和激活破骨细胞。对已公开的小鼠骨髓基质细胞单细胞RNA测序(scRNAseq)数据的分析表明,Tnfsf11+细胞表达了高水平的Mmp13、Limch1和Wif1,证实了它们的骨生成细胞身份。ISH证实了Mmp13和Tnfsf11在药物和OPG:Fc处理的小鼠骨表面细胞中的共表达。在人/鼠骨的生理条件下,RANKL主要由破骨细胞附近的骨生成细胞表达,而OPG主要由成骨细胞和成骨细胞表达。
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来源期刊
Bone Research
Bone Research CELL & TISSUE ENGINEERING-
CiteScore
20.00
自引率
4.70%
发文量
289
审稿时长
20 weeks
期刊介绍: Established in 2013, Bone Research is a newly-founded English-language periodical that centers on the basic and clinical facets of bone biology, pathophysiology, and regeneration. It is dedicated to championing key findings emerging from both basic investigations and clinical research concerning bone-related topics. The journal's objective is to globally disseminate research in bone-related physiology, pathology, diseases, and treatment, contributing to the advancement of knowledge in this field.
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