TNFSF11/RANKL: A Key Regulator of Bone Metabolism and Beyond

Molecular Structure and Expression

TNFSF11 also called RANKL is a cytokine that is a member of tumor the necrosis factor super family. This protein is released in two forms one is transmembrane and other is soluble and full form of membrane bound protein is 316 amino acids. RANKL is mainly synthesized by osteoblasts, osteocytes and activated T-cells. RANKL gene is mapped on chromosome 13q14 and the expression of this gene is controlled by several factors such as vitamin D, parathyroid hormone and cytokines. The protein is a homotrimer and this is because it is the only way that the receptor can be bound.

The RANK/RANKL/OPG Axis

The actions of RANKL are mediated by its binding to its receptor RANK, and its activity is modulated by osteoprotegerin, a decoy receptor. This interrelationship of RANK/RANKL/OPG axis is important in the regulation of bone remodelling and imbalances in this system have been implicated in the pathogenesis of osteoporosis. When RANKL engages with RANK on osteoclast precursor cells, it initiates a series of events that results in osteoclast differentiation and function. OPG that is synthesized by osteoblasts and other cells is a cytokine that can latch to RANKL and thus avoid its binding to RANK and thus osteoclastogenesis is suppressed. RANKL and OPG levels have to be in a certain ratio for bone homeostasis to be maintained.

Molecular Mechanisms and Signalling Pathways

At the molecular level, RANKL works through binding of its receptor RANK which is largely expressed on the osteoclast precursor cells. This binding results into setting off a series of cellular signalling that results in the activation of NF-κB, MAPKs, and calcium signalling. The RANKL-RANK interaction mechanism at the molecular level involves several proteins and downstream signals. During receptor binding, TRAF6 gets loaded which results in a series of phosphorylation and ubiquitination processes. These molecular processes finally result in the activation of transcription factors that controls osteoclast differentiation, survival and activity. Besides bone metabolism, this signalling pathway also affects the function of immune cells especially in RANKL-RANK interaction T cell is mediated a very immune precise complex responses manner mechanism and thereby that lymph demonstrating couple’s node the bone organogenesis.

Physiological and Pathological Roles in Bone Remodelling

RANKL serves as a pivotal molecular mediator in bone remodelling, orchestrating the delicate balance between bone formation and bone resorption. It is a cytokine that is mainly synthesized by osteoblasts, osteocytes, and T-cells that get activated; RANKL induces osteoclastogenesis and osteoclast function. RANKL bone expression homeostasis is as tightly such regulated control in of normal RANKL cells levels to determines maintain the rate of bone turnover. In pathological conditions, there is an imbalance in the RANKL signalling pathway, and this results in bone diseases. Osteoporosis is a disease that is defined by low bone mass and increased risk of fractures, and it is linked with alterations in RANKL signalling. Menopausal women especially have high RANKL levels because of low estrogen levels which enhances bone resorption and reduces bone density. Also, inflammatory diseases such as rheumatoid arthritis involve high levels of RANKL that leads to bone loss and joint destruction.

Immunological and Cancer-Related Implications

The biological relevance of RANKL is not confined to bone, it also plays roles in the immune system and cancer. In the context of the immune system, RANKL is essential for lymph node formation, regulation of T cell – dendritic cell interactions and the maintenance of immune tolerance. T regulatory cells as well as activated T cells secrete RANKL which indicates that it might be involved in the regulation of the immune response and inflammation.

Cancer cells can exploit RANKL signalling to create favourable microenvironmental conditions that support tumor growth and metastasis. Particularly in breast, prostate, and lung cancers, elevated RANKL levels correlate with increased bone metastasis and poor prognosis.

Suitable ELISA Kits

• TNFSF11/RANKL ELISA Kit
• RANK ELISA Kit