Third party funded individual grant
Acronym: ODE
Start date : 01.04.2021
End date : 31.03.2026
The ODE project will provide new understanding about the sensitive balance of bone homeostasis, and how stress factors in bone such as inflammation and reduced vascularization influence the viability of osteocytes. We will decipher in detail which impact the death of osteocytes has on the bone environment and bone strength and how we can avoid this negative influence. On a broader scale, we can use the gained knowledge to better understand the pathogenesis of bone loss and discover potential new pathways that might be targeted in the future to prevent bone loss from happening.
Osteocytes are long-lived cells within the bone matrix that have a variety of functions in the control of bone remodeling. They mediate the systemic regulation of the mechanical loading-induced bone renewal. Because osteocytes are important producers of RANKL, they are considered as strong activators of bone resorption. Osteocyte death is happening with age, after menopause or under pathological conditions such as micro-fracture or osteonecrosis. Furthermore, bone resorption is markedly enhanced by the induction of osteocyte death. Despite evidence that osteocyte death induces osteoclastogenesis by released of RANKL, other mechanisms including the expansion of damage-associated molecular patterns (DAMPs) within the micro-environment have not been fully delineated yet. Recently,Macrophage inducible Ca 2+ -dependent lectin receptor (Mincle) dependent manner. These findings suggest a hitherto unknown connection between osteocyte death and C-type lectin receptor dependent osteoclastogenesis, which might regulate bone remodeling in fracture healing and osteonecrotic disease. My proposal aims to clarify the link between osteocyte death pathways and stimulation of osteoclasts. I specifically aim to characterize in which way osteocytes die within the bone matrix (apoptosis, necrosis, necroptosis, ferroptosis or pyroptosis ), which specific DAMPs are released into the bone marrow via the canalicular network. In this context, fracture, osteonecrosis and inflammatory disease-induced osteocyte death will be analyzed. In particular, I will molecularly characterized osteocyte cell death and block their dying pathway. Next, I will determine putative molecular mechanisms driving osteoclast maturation through the pathways triggered by myeloid specific C-type lectin receptors such as Mincle, and Dectins.Finally, I will verify the molecular mechanisms of osteocyte death-induced osteoclastogenesis also in human patients suffering from osteonecrosis (jaw and femoral head) or rheumatoid arthritis induced bone loss. These experiments have a clear translational impact on the development of new therapeutic avenues for not only osteoporosis, but also fracture, osteonecrosis and inflammatory bone loss treatment.