Interleukin-6 and tumor necrosis factor-α in osteoimmunology: Aging, and anticytokine therapies

Table 2 Disease contexts and associated osteoimmunological mechanisms

Disease context	Key IL-6/TNF-α mechanisms described in the manuscript
Postmenopausal/senile osteoporosis	Estrogen deficiency and immunosenescence increase IL-6 and TNF-α; IL-6 drives RANKL expression via JAK/STAT; TNF-α stimulates osteoclastogenesis via NF-κB/MAPK; cytokine levels correlate with bone turnover markers (PINP, CTX)
Rheumatoid arthritis & inflammatory bone disease	Cytokine-rich synovium; TNF-α and IL-6 drive osteoclast activity at the pannus–bone interface, causing juxta-articular osteopenia and periarticular erosions; RANKL/OPG ratio shifts toward resorption
Osteoarthritis	IL-6 signaling drives cartilage degradation and subchondral bone remodeling
Periodontitis	Chronic local inflammation with RANKL-mediated alveolar bone resorption and osteoclast activation
Osteosarcopenia (bone-muscle axis)	TNF-α and IL-6 mediate muscle wasting (inhibited myogenic differentiation, protein degradation, suppressed IGF-1) and bone loss, creating a bidirectional cycle of frailty, falls and fracture risk

PINP: Procollagen type I N-terminal propeptide; CTX: C-terminal telopeptide; IGF-1: Insulin-like growth factor-1; IL-6: Interleukin-6; TNF-α: Tumor necrosis factor-α; RANKL: Receptor activator of NF-κB ligand; JAK: Janus kinase; STAT: Signal transducer and activator of transcription; MAPK: Mitogen-activated protein kinase; NF-κB: Nuclear factor κB; OPG: Osteoprotegerin.