Towards Control Over the Dynamic Equilibrium of Bone Tissue Maintenance

Bone loses mass and strength with age, leading to the condition called osteoporosis. The extracellular matrix of bone is dynamically remodeled throughout life, built up osteoblast cells and broken down by osteoclast cells. Osteoporosis is the result of a growing imbalance in cell activity and cell creation that favors osteoclasts. There are many contributing causes, and some uncertainty of which of these causes are more or less important. The chronic inflammation that accompanies aging does appear to be important, particularly that connected to the senescence-associated secretory phenotype (SASP) of senescent cells.

Given that osteoporosis is an imbalance, there are many potential ways to treat the condition, only some of which address the root causes. Any methodology that enhances osteoblast activity to a suitable degree or suppresses osteoclast activity to a suitable degree should be compensatory and beneficial, all other things remaining equal. That said, one would expect targeting the root causes of the imbalance to be a better approach, more likely to produce a larger effect size, and likely to have other beneficial effects elsewhere in the body. For example, the use of senolytic drugs to remove senescent cells is beneficial in many ways beyond the plausibly beneficial impact of a reduced SASP on processes of bone maintenance.

Current advances in regulation of bone homeostasis

Bone homeostasis in the adult skeleton is complex processes. Human skeletal tissue is a constant state of remodelling. The three main bone cells involve in this remodelling process - osteoblasts, osteoclasts and osteocytes via regulation of molecular signalling pathways. In bone remodelling, the discrete zones of bone are resorbed by osteoclasts and substituted by fresh bone by osteoblasts, allowing for repair of bone micro-injury and adapting of bone niche for control of mechanical strengths.

Osteoblast cells are energetic in protein synthesis and matrix secretion to preserve and form new healthy bones. Following mineralization of bone matrix, fully differentiated and matured osteoblasts become osteocytes and are implanted in the bone matrix. During bone remodelling process, mechanosensory cells, osteocytes act as bone orchestrators. This remodelling process is regulated by several local (e.g., growth factors, cytokines, chemokines) and systemic (e.g., estrogens) factors that all together subscribe for bone homeostasis.

In bone modelling process, i.e., during bone development and bone resorption stages, osteocytes act autonomously to fine-tune bone structure. Interestingly, in bone remodelling process, these cells act recycler to restore and keep skeletal health. After osteoclast-mediated bone resorption sequence, the eroded surface of trabecular bone is engaged by osteoblasts that make bone matrix and then undertake mineralization. Under normal physiological conditions of bone homeostasis, osteoclastic action is closely associated with osteoblastic action in such a way that the eroded bone is completely exchanged by fresh bone. Definitively, fluctuating this homeostatic equilibrium in favour of excessive osteoclast activity turns to bone pathological conditions such as osteoporosis, Paget's disease, rheumatoid arthritis (RA), osteoarthritis, and autoimmune arthritis.

Osteoporosis can be prevented and improved musculoskeletal health by using numerous pharmacotherapies such as biphosphonates; selective estrogen receptor modulators (SERMs); hormone therapies; strontium ranelate; denosumab (a human monoclonal antibody with specificity for RANKL); romosozumab (a monoclonal antibody that binds to and inhibits sclerostin) or stimulating bone formation called anabolic medications e.g., PTH preparations and calcitonin therapy have been verified the effects of increased bone mineral density and decreased risk of skeletal fractures.

However, these treatments have some side effects, such as oily skin, fluid retention, nausea, long-term toxicity, and even prostate cancer in males and thus natural therapies that incur better therapeutic activities and fewer side effects are hunted. Therefore, searching for small molecules that precisely suppress osteoclastic action is a favourable approach of the drug discovery for the treatment and management of bone-related diseases including osteoporosis.

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