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Molecular control of the bilateral communication between osteoclasts and osteoblasts

破骨细胞和成骨细胞双边通讯的分子控制

基本信息

批准号：
276722096
负责人：
Professor Dr. Michael Amling
金额：
--
依托单位：
Institut für Osteologie und Biomechanik (IOBM)
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2015
资助国家：
德国
起止时间：
2014-12-31 至 2018-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/276722096?language=en
关键词：
Molecular control bilateral communication between

项目摘要

The bone matrix is constantly remodeled through the balanced activities of two cell types, bone-forming osteoblasts and bone-resorbing osteoclasts. Despite the fact that both cell types are fundamentally different, there is hallmark evidence for a bilateral communication between osteoblasts and osteoclasts. In fact, while osteoblasts are the main producers of the two most relevant regulators of bone resorption (Rankl and Opg), osteoclasts are known to produce osteonabolic molecules, which remain to be clearly identified. One hormone utilizing the communication between the two bone remolding cell types is parathyroid hormone (PTH), which binds to its receptor on osteoblasts to induce the expression of the pro-osteoclastogenic cytokine Rankl.In a previous project sponsored by the DFG we could show that the hormone calcitonin (CT) mediates a negative influence on bone formation through binding to its receptor (CTR) on osteoclasts. At the molecular level this indirect influence is explained by the fact that CT inhibits the osteoclastic expression of Spns2, a transporter facilitating secretion of the osteoanabolic lipid mediator sphingosine-1-phosphate (S1P). We could further show that S1P levels are increased in bone tissue from CT- and CTR-deficient mice, and that the elevated bone formation rate in CTR-deficient mice is normalized by additional deletion of the S1P receptor S1P3. In additional studies we could show that PTH does not only induce expression of Rankl in osteoblasts, but also its release into the medium, which might represent a relevant mechanism, as Rankl is synthesized as a transmembrane protein.Within the present project we want to address three questions regarding the bilateral communication between osteoblasts and osteoclasts. 1) Which receptor mediates the osteoanabolic influence of S1P? Here we will primarily utilize a mouse model lacking the S1P-degrading enzyme S1P-lyase, where we have observed a markedly increased bone mass. 2) Does the release of S1P by osteoclasts explain, why patients with excessive osteoclastogenesis display bone marrow fibrosis? Here we could already show that S1P-treated macrophages release molecules inducing the expression of fibrotic markers in mesenchymal bone marrow cells. 3) By which mechanism does PTH promote Rankl release into the medium? We hypothesize that PTH does not only induce expression of Rankl, but also of a Rankl-processing endopeptidase.

骨基质通过两种细胞类型（骨形成成骨细胞和骨吸收破骨细胞）的平衡活动不断重塑。尽管事实上这两种细胞类型是根本不同的，有标志性的证据成骨细胞和破骨细胞之间的双边通信。事实上，虽然成骨细胞是两种最相关的骨吸收调节剂（Rankl和Opg）的主要生产者，但已知破骨细胞产生骨代谢分子，其仍有待明确鉴定。利用两种骨重塑细胞类型之间的通信的一种激素是甲状旁腺激素（PTH），其与成骨细胞上的其受体结合以诱导前破骨细胞生成细胞因子Rankl的表达。在DFG赞助的先前项目中，我们可以表明激素降钙素（CT）通过与破骨细胞上的其受体（CTR）结合来介导对骨形成的负面影响。在分子水平上，这种间接影响可以通过CT抑制Spns 2的骨细胞表达来解释，Spns 2是一种促进骨合成代谢脂质介质鞘氨醇-1-磷酸（S1 P）分泌的转运蛋白。我们可以进一步表明，在CT和CTR缺陷小鼠的骨组织中，S1 P水平增加，并且通过额外缺失S1 P受体S1 P3使CTR缺陷小鼠中升高的骨形成率正常化。在另外的研究中，我们可以表明，PTH不仅诱导成骨细胞中的Rankl的表达，而且其释放到介质中，这可能是一个相关的机制，因为Rankl是作为一个跨膜蛋白合成的。1)哪种受体介导S1 P对骨合成代谢的影响？在这里，我们将主要利用缺乏S1 P-降解酶S1 P-裂解酶的小鼠模型，我们观察到骨量显著增加。2)破骨细胞释放S1 P能否解释为什么破骨细胞过度生成的患者会出现骨髓纤维化？在这里，我们已经可以表明，S1 P处理的巨噬细胞释放诱导间充质骨髓细胞中纤维化标志物表达的分子。3)PTH通过何种机制促进Rankl释放到培养基中？我们假设PTH不仅诱导Rankl的表达，而且诱导Rankl加工内肽酶的表达。