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

Table 1 Interleukin-6 versus tumor necrosis factor-α signaling pathways in bone cells

Feature	IL-6	TNF-α
Receptors/signaling	Classical signaling via membrane IL-6R and gp130; trans-signaling via soluble IL-6R gp130 complex on gp130-expressing cells; acts through STAT3 and ERK1/2	TNFR1 (55 kDa, widely expressed, proinflammatory/proapoptotic) and TNFR2 (75 kDa, limited expression, cell survival/proliferation); activates NF-κB and MAPK
Effect on osteoclasts	Trans-signaling enhances osteoclastogenesis, mainly by increasing RANKL expression on stromal cells and osteoblasts	Promotes osteoclast precursor growth and differentiation via RANKL-dependent and RANKL-independent mechanisms; can induce osteoclast formation even without RANKL
Effect on osteoblasts	Classical signaling can promote osteoblast development and physiological remodeling under low-RANKL conditions	Suppresses osteoblastogenesis, chiefly by inducing apoptosis of osteoblast precursors and mature osteoblasts through TNFR1
Net effect on bone	Depends on balance of classical vs trans-signaling; trans-signaling is associated with pathological bone loss	Dual catabolic action: Promotes resorption while preventing formation

IL-6: Interleukin-6; TNF-α: Tumor necrosis factor-alpha; RANKL: Receptor activator of NF-κB ligand; NF-κB: Nuclear factor-κB; IL-6R: IL-6 receptor; MAPK: Mitogen-activated protein kinase; TNFR: TNF receptor.

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.

Table 3 Anticytokine therapies and skeletal outcomes described in the manuscript

Agent(s)	Target	Skeletal effects reported
Etanercept	TNF-α (decoy receptor-Fc fusion protein)	Lowers osteoclast activity, maintains bone mineral density, slows radiographic erosion progression
Infliximab, adalimumab	TNF-α (monoclonal antibodies)	Neutralize soluble and membrane-bound TNF-α; osteoprotective effects alongside disease control
Tocilizumab, sarilumab	IL-6 receptor	Disrupt IL-6 signaling and JAK/STAT activation, reduce osteoclastogenesis, lower bone turnover markers, and may protect bone comparably to anti-TNF in some settings

Reported fracture-reduction estimates from observational studies should be interpreted cautiously, as noted in the text. BMD: Bone mineral density; IL-6: Interleukin-6; TNF-α: Tumor necrosis factor-α; JAK: Janus kinase; STAT: Signal transducer and activator of transcription; TNF: Tumor necrosis factor.

Table 4 Emerging and experimental therapies with current evidence level

Strategy	Representative agents/approach	Current evidence level (per manuscript)
Senolytics/SASP modulation	Dasatinib + quercetin (D+Q), navitoclax, fisetin	Preclinical (murine) efficacy; early-stage human trials show reduced inflammatory biomarkers and improved physical function, but no conclusive skeletal benefit established in humans
Downstream pathway inhibition	NF-κB/IKK inhibitors; JAK inhibitors (baricitinib, tofacitinib, upadacitinib)	JAK inhibitors reduce bone erosion in RA trials; NF-κB inhibitors effective in preclinical models; long-term safety surveillance required
Combination therapy	Anti-cytokine agent with anabolic agents (PTH analogs teriparatide/abaloparatide; romosozumab)	Preliminary/investigational; small studies (e.g., tocilizumab + romosozumab) suggest added benefit; requires confirmation in adequately powered trials
Dual cytokine inhibition	Combined TNF-α and IL-6 blockade	Conceptual; requires extensive safety evaluation due to cumulative immunosuppression
Precision/biomarker-guided therapy	Cytokine profiling, pharmacogenomics (SNPs), multi-omics, circulating miRNAs/exosomal markers, machine learning	Emerging; predictive biomarkers require validation in prospective trials

IKK: Inhibitor of IκB kinase; SASP: Senescence-associated secretory phenotype; NF-κB: Nuclear factor-κB; JAK: Janus kinase; RA: Rheumatoid arthritis; PTH: Parathyroid hormone; TNF-α: Tumor necrosis factor-α; IL-6: Interleukin-6; SNP: Single-nucleotide polymorphism.