Molecular control of the bilateral communication between osteoclasts and osteoblasts

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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.