Translational perspectives of next-generation cytokine therapies for musculoskeletal disorders.

Musculoskeletal disorders (MSDs) are a leading cause of chronic pain and disability worldwide, yet available pharmacological treatments remain largely ineffective or palliative. Increasing evidence indicates that chronic inflammation in MSDs reflects not only excessive pro-inflammatory signaling but also impaired endogenous anti-inflammatory and pro-resolving mechanisms. In this context, cytokines IL-34 through IL-41 have recently emerged as important regulators of immune activation, tissue remodeling, and tissue regeneration. This review provides a mechanistically informed analysis of the roles of IL-34-IL-41 in the pathogenesis of major MSDs, including inflammatory arthritis, osteoarthritis, osteoporosis, intervertebral disc degeneration, and sarcopenia. A functional dichotomy within this cytokine spectrum is highlighted: IL-34, IL-36, IL-39, and IL-40 act as pro-inflammatory or inflammation-amplifying mediators that promote macrophage activation, osteoclastogenesis, and autoimmune responses, whereas IL-35, IL-37, IL-38, and IL-41 exert anti-inflammatory and pro-resolving effects by suppressing Th1/Th17-driven immunity and fostering regulatory immune phenotypes. Notably, IL-41 also integrates immune modulation with metabolic regulation and muscle repair. We discuss emerging translational strategies targeting this cytokine group and address key unresolved questions related to cytokine redundancy, disease heterogeneity, patient stratification, and safety. Collectively, the available evidence highlights the growing mechanistic and translational relevance of cytokines IL-34 through IL-41 in MSDs.