Effect of senescence on bone remodeling: the role of inflammageing.

"Osteoporosis is a major cause of morbidity and mortality in older people. Osteoporosis is characterized by low bone mass and microarchitectural deterioration of bone tissue with a subsequent increase in bone fragility and susceptibility to fractures. There are a large number of risk factors for the development of senile osteoporosis. However, recent discoveries suggest that inflammageing, i.e. the immunological inflammatory profile characterizing immune senescence, plays a major role in bone remodelling through pro-inflammatory cytokines, which are able to influence osteoclasts and osteoblasts. Therefore ageing induces osteoporosis through immunologically mediated modulation of bone remodelling. It is the activated immune profile which, through inflammation and inflammatory cytokine production, modulates osteoblast and osteoclast activity leading to osteoporosis. Senile osteoporosis is an example of the central role of immune-mediated inflammation in determining bone resorption. Here we discuss the pathogenesis of osteoporosis in the context of immunosenescence and focus on therapeutic strategies targeting osteoimmunology pathways. Osteoimmunology is an emerging research area that deals with the mutual interactions between bone and the immune system. Osteoclast, the sole resorbing bone cell, is the center of attention in osteoimmunological research, due to its haematopoietic origin and strong activation through cytokines. However, novel functions of osteoblasts, specialized in bone formation, and osteocytes, the structural bone cells, have also been recently unraveled. Critical proteins with osteoimmune functions, including the pro-osteoclastic cytokine receptor activator of NF-ĸB ligand and inhibitors of the pro-osteoblastic Wnt signaling pathway, recently showed roles of paramount importance in both inflammageing and osteoporosis. The combined effects of estrogen deprivation and raising of FSH production occurring in menopause cause a marked stimulation of bone resorption and a rapid bone loss which is central for the onset of postmenopausal osteoporosis and chronic inflammatory diseases. These discoveries have also led to the development of targeted therapies to counteract not only inflammation-induced bone loss but also postmenopausal and senile osteoporosis. Ageing also affects bone through the production of myeloid cells in bone marrow, a condition associated with increased chronic inflammation by macrophages and decreased bone mass due to excess bone resorption by osteoclasts. The ageing of both haematopoietic stem cells and bone marrow microenvironment, emerging from increased oxidative stress, peroxisome proliferator-activated receptor γ activity and adipogenesis in the ageing bone marrow, contribute to impaired osteoblastogenesis and niche cell function. Anti-ageing interventions targeting mesenchymal stem cell differentiation in the bone marrow could enhance osteoblastic bone formation and counteract inflammation and osteoclastic bone loss. The inducer cells in senile osteoporosis are immune cells, such as activated macrophages and lymphocytes, which produce cytokines and soluble mediators able to stimulate osteoclast differentiation and activation. Molecules that regulate osteoclastogenesis are key factors in many immunological functions. Osteoporosis and inflammageing share the same immunological profile. Osteoclastogenesis and inflammation are directly proportional to osteoclast precursor levels in peripheral blood. Characteristic of an agedi mmune profile is the accumulation of activated memory cells expressing RANKL, preferentially resident in the bone and secreting osteoclastogenic proinflammatory cytokines. The immunophenotypical analysis of peripheral blood lymphocyte subsets confirms the deep involvement of the immune system in bone remodelling. CD3+ T lymphocytes are increased in osteoporotic patients, as well as their CD4+\/CD8+ ratio, whereas CD20+ B lymphocytes are significantly decreased. Moreover, the CD8+CD56+ lymphoid subset including killer\/effector lymphocytes producing large amounts of the inflammatory cytokine TNF-α, is also expanded. In osteoporotic patients, as well as in elderly people, there is an increase in CD45RO+ memory lymphocytes, whereas the CD45RA+ naive subset is markedly decreased. Another important mechanism which could link inflammageing and osteoporosis is the dysregulation of T-regulatory cells producing soluble factors IL-10 and TGF-β, both able to antagonize immune media tedbone resorption.. . . . . . . . . "