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

Abstract

Interleukin (IL)-6 and tumor necrosis factor (TNF)-α are key osteoimmunology cytokines that have extensive effects on bone remodeling and play a role in dysregulation in aging and inflammatory diseases. Both molecules affect the survival of osteoblasts (OBs), differentiation of osteoclasts (OCs), and osteocyte functions via pathways that include nuclear factor (NF)-κB activation, receptor activator of NF-κB ligand (RANKL)/osteoprotegerin imbalance, and dual IL-6 signaling (classical vs trans-signaling). All these mechanisms lead to bone resorption and hamper formation. Within the inflammaging context, the senescence-associated secretory phenotype (SASP) increases IL-6 and TNF-α, which stimulate immunosenescence, osteoporosis, rheumatoid arthritis erosions, and osteosarcopenia. This is a narrative review. The literature was identified through nonsystematic searches of PubMed and Google Scholar using terms related to IL-6, TNF-α, osteoimmunology, inflammaging, and anticytokine therapy, and relevant articles were selected and synthesized qualitatively. The review examines the IL-6 and TNF-α mechanistic pathways and crosstalk in osteoimmunology. It analyzes the pathogenic processes such as T-cell-derived RANKL, macrophage polarization changes, and OB apoptosis induced by TNF receptor 1 and IL-6 trans-signaling as well as assessing the aging immune alterations. This cytokine-induced crosstalk enhances RANKL production by stromal cells, osteocytes, and Th1 lymphocytes, and aging augments these effects due to myeloid bias and T regulatory cell dysfunction, ultimately decreasing bone mineral content and predisposing bone to fractures, as observed in postmenopausal osteoporosis and periodontitis. Anti-TNF- (etanercept and adalimumab) and anti-IL-6 (tocilizumab) therapeutic interventions that suppress OC activity, increase OB activity, and improve microarchitecture restore bone homeostasis. Observational studies have reported a lower fracture incidence with such therapies, although this estimate derives from nonrandomized data and warrants cautious interpretation. IL-6 interaction with TNF-α is the core principle of bone–immune crosstalk in aging and inflammation. New modalities are senolytics of SASP clearance, Janus kinase/NF-κB inhibitors, and precision medicine based upon cytokine profiling. Despite the promising results, there is still a problem with pharmacokinetics and safety in elderly patients. The interaction between IL-6 and TNF-α in bone–immune crosstalk is critical to further developing targeted interventions to counteract bone loss in old age and inflammation and enhance personalized treatment plans.

Keywords: Receptor activator of NF-κB ligand/osteoprotegerin axis; Janus kinase/NF-κB; Osteoprotegerin; Inflammaging; Senolytics

Core Tip: Interleukin (IL)-6 and tumor necrosis factor (TNF)-α are important cytokines that have been implicated in the pathogenesis of bone loss by means of an imbalance of receptor activator of nuclear factor (NF)-κB ligand/osteoprotegerin, NF-κB activation, and osteoclast encouragement. They are aggravated by inflammatory bone diseases and osteoporosis caused by inflammaging and senescence-associated secretory phenotype. Their crosstalk promotes bone resorption by dysregulating immune cells. Anti-TNF-α and anti-IL-6 treatments normalize bone homeostasis, and observational data suggest a lower reduction in fracture occurrence, an estimate that should be interpreted cautiously given its non-randomized basis. These novel methods include senolytics, Janus kinase, and cytokine-based precision medicine.