Molecular Structure and Expression

• TNFSF11, also known as RANKL, is a cytokine in the tumor necrosis factor superfamily.
• Exists in two forms: transmembrane and soluble, with the full membrane-bound form being 316 amino acids.
• Synthesized by osteoblasts, osteocytes, and activated T-cells.
• Gene located on chromosome 13q14, regulated by factors like vitamin D, parathyroid hormone, and cytokines.
• Protein forms a homotrimer, essential for receptor binding.

The RANK/RANKL/OPG Axis

• RANKL binds to its receptor RANK, with its activity modulated by osteoprotegerin (OPG), a decoy receptor.
• This axis is crucial for bone remodelling regulation.
• Imbalances in this system linked to osteoporosis pathogenesis.
• RANKL binding to RANK on osteoclast precursor cells triggers osteoclast differentiation and function.
• OPG prevents RANKL from binding to RANK, suppressing osteoclastogenesis.
• Proper ratio of RANKL to OPG is necessary for bone homeostasis.

Molecular Mechanisms and Signalling Pathways

• RANKL binding to RANK on osteoclast precursor cells activates NF-κB, MAPKs, and calcium signalling.
• TRAF6 is involved in receptor binding, leading to phosphorylation and ubiquitination processes.
• Activates transcription factors controlling osteoclast differentiation, survival, and activity.
• Also affects immune cell function, coupling bone remodelling with immune responses and lymph node organogenesis.

Physiological and Pathological Roles in Bone Remodelling

• RANKL is pivotal for bone remodelling, balancing bone formation and resorption.
• Synthesized by osteoblasts, osteocytes, and activated T-cells, inducing osteoclastogenesis.
• RANKL expression is tightly regulated to maintain bone homeostasis.
• Imbalances in RANKL signalling lead to bone diseases like osteoporosis, characterized by low bone mass and fracture risk.
• Menopausal women have high RANKL levels due to low estrogen, increasing bone resorption and reducing bone density.
• Inflammatory diseases like rheumatoid arthritis involve high RANKL levels, leading to bone loss and joint destruction.

Immunological and Cancer-Related Implications

• Beyond bone, RANKL plays roles in the immune system and cancer.
• Essential for lymph node formation, T cell-dendritic cell interactions, and immune tolerance maintenance.
• T regulatory cells and activated T cells secrete RANKL, indicating its role in immune response regulation and inflammation.
• Cancer cells exploit RANKL signalling for favorable microenvironmental conditions, supporting tumor growth and metastasis.
• Elevated RANKL levels correlate with increased bone metastasis and poor prognosis in breast, prostate, and lung cancers.