Irisin, Sclerostin, and Inflammatory Axis: Implication in Bone‐Muscle Wasting Diseases

Abstract

Bone-muscle diseases, such as osteoporosis, rheumatoid arthritis, sarcopenia and cachexia, represent a growing global health concern, particularly among aging populations and older adults. These multifactorial disorders are characterized by progressive decline in bone density and muscle mass, increasing the chances of immobility and eventually disability. Such manifestations are driven by a complex molecular crosstalk between bones and muscles. This review highlights the key role of the irisin-sclerostin-inflammation triad in the pathophysiology of musculoskeletal degeneration. Irisin is a myokine induced by exercise. It is associated with osteogenesis and muscle regeneration. Sclerostin is an osteocyte-derived Wnt antagonist, inhibits bone formation and is linked to impaired muscle regeneration. Inflammatory mediators such as TNF-α and IL-6 drive muscle catabolism and bone resorption through the NF-κB and STAT3 signaling pathways. Dysregulation of this triad accelerates musculoskeletal degeneration, particularly in chronic diseases and aging. We described the correlation between these diseases and mediators with age and gender. Additionally, we discussed current and emerging therapeutic strategies targeting these mediators, including anti-sclerostin antibodies for high-risk osteoporosis, cytokine/JAK-pathway inhibitors for inflammatory disease, and structured resistance/weight-bearing exercise as a cornerstone intervention. We highlighted assay standardization needs, proposed human-focused models, and outlined priorities for precision, combination strategies targeting the triad in bone-muscle wasting disorders.