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.