Senescent cells accumulate with age, causing tissue dysfunction throughout the body via their inflammatory secretions. One of those dysfunctions is the age-related imbalance in bone remodeling, favoring the osteoclasts that break down bone tissue at the expense of the osteoblasts that rebuild it. The result is osteoporosis, the characteristic loss of bone mass and resilience that takes place with age. It has been clear for some years now that clearing senescent cells in aged individuals is a potential basis for the treatment of osteoporosis, producing a reversal of the condition in animal models treated in this way. This outcome is accompanied by a range of supporting evidence, as discussed here.
Osteoporosis is a frequent age-related disease that results from a dysregulation of the activities of osteoclasts and osteoblasts. As in other age-related diseases, research in the last decade has clearly provided evidence for a role of senescence in age-related osteoporosis. In pioneering work the expression of the senescent cell biomarker p16Ink4 was shown to increase in bone-derived B cells, T cells, myeloid cells, osteoprogenitors, osteoblasts, and osteocytes from young versus old male and female mice. Moreover, osteocytes and myeloid cells were identified as the cell populations with the most pronounced upregulation of senescence-associated secretory phenotype (SASP) factors within the bone environment.
Accumulation of senescent cells in the context of age-related and radiotherapy-related bone loss was since then confirmed by others, and was also shown in bone biopsy samples from older postmenopausal compared to younger premenopausal women. A causative role of senescent cells in mediating age-related bone loss was finally evidenced by pharmacological clearance of senescent cells in old mice or genetic clearance of senescent cells by inducible elimination of p16Ink-4a-expressing senescent cells using INK-ATTAC transgenic mice. The positive effect on bone microarchitecture and bone strength observed in these models after clearance of senescent cells was shown to be mediated partly by the elimination of senescent osteocytes. Moreover, increased bone formation by osteoblasts and a reduction in bone marrow adipose tissue was seen, and thereby supported a shift in bone marrow-derived mesenchymal stem cell (BMSC) differentiation from osteoblasts to adipocytes as mechanism of senescence mediated age-related bone loss
Taken together, a major focus in recent research has been on the role of senescence in BMSC proliferation and differentiation, and major progress has been made in elucidating potential regulators of senescence-mediated bone loss in age-related osteoporosis. This knowledge provides an important foundation for an in-depth understanding of the application of already existing senescence-based therapeutic options in the treatment of osteoporosis. Furthermore, by closing the gaps, in future, novel therapeutic options with a more specific and individualized approaches may arise.