PRAGYA SANTRA, AMITY UNIVERSITY KOLKATA
Normally osteocyte apoptosis is the default fate to remove dead bone cells and its self-renewal for preserving the strength. But at times the apoptosis gives rise to pathological conditions of ageing, fatigue, inflammation, decreased bone mineral density, ultimately bone loss. Osteocytes surgery often induces osteoporosis resulting in bone microstructure and mechano-transduction in the diphtheria toxin receptor.
Bone ageing alters osteocytic lacunar-canalicular network (LCN), further increasing osteocyte loss due to decreased provision for nutrients. Also, the shape of osteocytes decreases and become spherical. Calcification of bone lacuna interrupts, the bone remodelling process making them more fragile and susceptible to fractures. Excessive production of reactive oxygen species (ROS) induces oxidative stress (OS) and causes DNA damage which leads to further bone apoptosis. Loss of stimuli leads to non-viability of osteocytes contributing to over-senescence and apoptosis.
Affected pulsatile fluid flow (PFF) disrupts LCN causing localised hypoxia in bones diminishing the nutrient supply in bones too. Reduction of mitophagy and increased uncoupling of the mitochondrion causes loss of mitochondrial ATP and decrease of intracellular pH to result in cellular damage. Mitochondria, the switchboard controlling the apoptosis machinery if once damaged amplify the ROS triggering rapid apoptosis.
Even hormonal imbalance causes severe consequences. Oestrogen deficiency originates osteocyte apoptosis, followed by a resorption-related bone loss by triggering OS activation in bone, including decreased antioxidant enzymes (AE) resulting in accumulation of apoptotic osteocytes. Many skeletal inflammatory diseases induce resorption-associated bone loss. Pro-inflammatory cytokines such as TNF-a and IL-6 leads to osteocyte apoptosis with deformities in the femoral head.
The key molecular mechanisms in promoting the osteocytic apoptosis are OS pathway and FAS/FASL pathway. Fas ligand binds to FASL, oligomerise and activates the novel death domain (DD) of the complex. It interacts with caspase-8, triggering caspase cascade to cause apoptosis.
Osteocyte cell death with subsequent mineralization microcytosis results in all the above consequences. Autophagy is a well-conserved mechanism for preserving osteocytic vitality. Starvation, a remarkable stimulus of autophagy promotes metabolites generation fuelling ATP, thus implicating osteocyte metabolism. Parathyroid hormone (PTH), having anti-apoptotic effect plays a major role in calcium homeostasis and check the ossification of bones. Recently discovered irisin hormone also inhibits apoptosis by regulating Caspase-9&3 expression. Mechanical stimuli also promote osteocyte viability via Src/MEK/ERK signal pathway activation.
Vital osteocytes are of paramount importance in preserving the mechanosensation and mechanoconduction of bone. Clinical anabolic drugs, such as teriparatide (PTH1-34)171, tetracycline172, and bisphosphonate173, etc., are prescribed for bone formation. Other potential mechanisms are still in progress to understand the disease and its remedy.
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SOURCES:
- Osteocyte apoptosis: the roles and key molecular mechanisms in resorption-related bone diseases, Jiang-Ying Ru and Yan-fen Wang, 12 October 2020, Cell Death & Disease- Nature, Volume 11, doi: https://doi.org/10.1038/s41419-020-03059-8Â
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