Summary
Osteocytes are long-lived cells within the bone matrix that have a variety of functions in the control of bone remodeling. They are the most frequent cells of the bone by far and mediate the regulation of the mechanical loading-induced bone renewal at the systemic level. Little is known how osteocytes die and how this process affects local bone homeostasis. Nonetheless several local bone diseases such as fracture, osteonecrosis and arthritis are characterized by enhanced osteocyte death and local bone resorption. My preliminary data show that osteocytes, when dying, undergo secondary necrosis, due to their secluded localization within the bone and the absence of phagocyting cells. Hence substantial amounts of damage-associated molecular patterns (DAMPs) are released into the bone micro-environment. I can show that DAMPs effectively osteoclast differentiation via binding to the C-type lectin receptor Mincle.
My proposal ODE aims to characterize osteocyte death, the nature of the released DAMPs and the molecular link between osteocyte death and stimulation of osteoclasts. I specifically aim to delineate, in which way osteocytes die within the bone matrix (apoptosis, necrosis, necroptosis, ferroptosis or pyroptosis) and which specific DAMPs are released into the bone marrow via the canalicular network. In this context, local bone diseases such as fracture, osteonecrosis and arthritis will be investigated. In aim 1, I will molecularly characterize osteocyte cell death and block the corresponding death pathways. In aim 2, I will determine putative molecular mechanisms driving osteoclast maturation through the pathways triggered by myeloid specific C-type lectin receptors. In aim 3, I will test the molecular mechanisms of osteocyte death-induced osteoclastogenesis. Overall, my proposal will gain new insights into local bone homeostasis, i.e. the molecular regulation of osteocyte death and the molecular links to an altered local bone microenvironment.
My proposal ODE aims to characterize osteocyte death, the nature of the released DAMPs and the molecular link between osteocyte death and stimulation of osteoclasts. I specifically aim to delineate, in which way osteocytes die within the bone matrix (apoptosis, necrosis, necroptosis, ferroptosis or pyroptosis) and which specific DAMPs are released into the bone marrow via the canalicular network. In this context, local bone diseases such as fracture, osteonecrosis and arthritis will be investigated. In aim 1, I will molecularly characterize osteocyte cell death and block the corresponding death pathways. In aim 2, I will determine putative molecular mechanisms driving osteoclast maturation through the pathways triggered by myeloid specific C-type lectin receptors. In aim 3, I will test the molecular mechanisms of osteocyte death-induced osteoclastogenesis. Overall, my proposal will gain new insights into local bone homeostasis, i.e. the molecular regulation of osteocyte death and the molecular links to an altered local bone microenvironment.
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More information & hyperlinks
| Web resources: | https://cordis.europa.eu/project/id/101001235 |
| Start date: | 01-06-2021 |
| End date: | 31-05-2026 |
| Total budget - Public funding: | 2 008 062,00 Euro - 2 008 062,00 Euro |
Cordis data
Original description
Osteocytes are long-lived cells within the bone matrix that have a variety of functions in the control of bone remodeling. They are the most frequent cells of the bone by far and mediate the regulation of the mechanical loading-induced bone renewal at the systemic level. Little is known how osteocytes die and how this process affects local bone homeostasis. Nonetheless several local bone diseases such as fracture, osteonecrosis and arthritis are characterized by enhanced osteocyte death and local bone resorption. My preliminary data show that osteocytes, when dying, undergo secondary necrosis, due to their secluded localization within the bone and the absence of phagocyting cells. Hence substantial amounts of damage-associated molecular patterns (DAMPs) are released into the bone micro-environment. I can show that DAMPs effectively osteoclast differentiation via binding to the C-type lectin receptor Mincle.My proposal ODE aims to characterize osteocyte death, the nature of the released DAMPs and the molecular link between osteocyte death and stimulation of osteoclasts. I specifically aim to delineate, in which way osteocytes die within the bone matrix (apoptosis, necrosis, necroptosis, ferroptosis or pyroptosis) and which specific DAMPs are released into the bone marrow via the canalicular network. In this context, local bone diseases such as fracture, osteonecrosis and arthritis will be investigated. In aim 1, I will molecularly characterize osteocyte cell death and block the corresponding death pathways. In aim 2, I will determine putative molecular mechanisms driving osteoclast maturation through the pathways triggered by myeloid specific C-type lectin receptors. In aim 3, I will test the molecular mechanisms of osteocyte death-induced osteoclastogenesis. Overall, my proposal will gain new insights into local bone homeostasis, i.e. the molecular regulation of osteocyte death and the molecular links to an altered local bone microenvironment.
Status
SIGNEDCall topic
ERC-2020-COGUpdate Date
27-04-2024
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