Role of C-type lectin molecules in bone homeostasis

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This project aims to understand how C-type lectin receptors such as Mincle and Dectin-1 affect the bone homeostasis. Normally, Mincle is associated with defense against fungal or bacterial infections. Recently, Mincle was found also important for tissue maintenance and tissue homeostasis after clearance of dead cells. Mincle is usually expressed by monocytes and macrophages. Since the bone resorbing cells, osteoclasts are a product of the fusion of myeloid progenitor cells, I hypothesized that Mincle could also play a role during bone tissue maintenance. In accordance with this hypothesis, the downstream pathway of C-type lectin receptors is associated with ITAM/FcRg and activation of SYK signaling, which was previously described as essential pathway for osteoclastogenesis. In support of this concept, preliminary analysis of Mincle knock-out mice and their littermate controls showed that Mincle knock-out mice are osteopetrotic likely due to fewer osteoclasts. In fact, Mincle is known to be activated by the binding of SAP130, a component of small nuclear ribonucleoprotein released during necrosis. Since late osteoblasts and osteocytes undergo necrosis during bone renewal, I assume that Mincle enhances osteoclastogenesis by sensing necrotic debris released by osteocytes and in this way increases bone loss. Hence, the aim of this application is: (1) to characterize the bone phenotype and the ability for osteoclast differentiation in mice lacking Mincle and mice lacking the other C-type lectin, Dectin-1; (2) to decipher the molecular mechanism, by which Mincle enhances osteoclast formation focusing on the process of dead osteocyte accumulation upon bone renewal, in vivo and in vitro; (3) to determine the importance of Mincle and Dectin-1 functions in osteoclasts during ovariectomy-induced osteoporosis and fracture healing and (4) to translate these findings into humans by determining the molecular mechanism of C-type lectin molecules in human osteoclasts. In summary, these experiments aim to unravel the role of C-type lectin receptors, Mincle and Dectin-1, in bone health and disease.