Rewiring osteoimmune homeostasis in osteoporosis: T-cell subsets as key regulators and emerging therapeutic targets
Abstract
Osteoporosis (OP) is a chronic metabolic bone disease characterized by reduced bone mass, microarchitectural deterioration, and an increased risk of fragility fractures. Although conventional views have emphasized the imbalance between osteoblasts and osteoclasts, advances in osteoimmunology have shown that T-cell subsets regulate bone remodeling through multilayered mechanisms, including the RANKL/RANK/OPG axis, inflammatory cytokine networks, costimulatory molecules, immune checkpoints, the gut microbiota, and cellular metabolic reprogramming. Th17 cells and their signature cytokine IL-17 promote RANKL expression and amplify the NF-κB/MAPK/NFATc1 pathway of osteoclast differentiation, thereby constituting a key pathogenic component in inflammatory bone loss and postmenopausal osteoporosis. In contrast, regulatory T cells (Tregs) inhibit osteoclast formation through Foxp3-, IL-10-, TGF-β-, CTLA-4- and IDO-related pathways, thereby limiting proinflammatory T-cell activation and maintaining bone marrow immune homeostasis. Th1/Th2 cells, CD8+ T cells, γδ T cells, T follicular helper cells, NKT cells, and mucosa-associated unconventional T cells may also influence bone resorption and formation in different pathological contexts through factors such as IFN-γ, TNF-α, IL-4, IL-13, IL-21, IL-22, and membrane-bound RANKL. Drawing on the literature concerning T-cell subsets, the Th17/Tregs and Th1/Th2 balances, γδ T cells, and the RANKL/OPG axis, this review provides a narrative…
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