Extra-osseous Roles of the RANK-RANKL-OPG Axis with a Focus on Skeletal Muscle

Abstract

Purpose of review: This review aims to consolidate recent observations regarding extra-osseous roles of the RANK-RANKL-OPG axis, primarily within skeletal muscle.

Recent findings: Preclinical efforts to decipher a common signalling pathway that links the synchronous decline in bone and muscle health in ageing and disease disclosed a potential role of the RANK-RANKL-OPG axis in skeletal muscle. Evidence suggests RANKL inhibition benefits skeletal muscle function, mass, fibre-type switching, calcium homeostasis and reduces fall incidence. However, there still exists ambiguity regarding the exact mechanistic actions and subsequent functional improvements. Other potential RANK-RANKL-OPG extra-osseous roles include regulation of neural-inflammation and glucose metabolism. Growing evidence suggests the RANK-RANKL-OPG axis may play a regulatory role in extra-osseous tissues, especially in skeletal muscle. Targeting RANKL may be a novel therapy in ameliorating loss of muscle mass and function. More research is warranted to determine the causality of the RANK-RANKL-OPG axis in extra-osseous tissues, especially those affected by aging.

Keywords: Denosumab; Extra-osseous; NF-κB signalling; Osteoprotegerin; RANK-RANKL-OPG axis; Skeletal muscle.

Fig. 1

The myogenic program of skeletal muscle (top) and potential points during myogenesis in which factors of the RANK-RANKL-OPG axis may affect skeletal muscle physiology (bottom). RANK-RANKL signalling may have the greatest effect on differentiated myoblasts, i.e., myotubes, as growing evidence suggests RANK expression is confined to myotubes. OPG may influence all stages of muscle regeneration, particularly earlier stages through its ability to bind to TRAIL, heparan sulfate proteoglycan (HSPs) and integrins. RANK-RANKL signalling may be a regulator of NF-κB dynamics, atrophy networks, inflammatory signals and Ca²⁺ homeostasis in skeletal muscle

Fig. 2

The OPG-RANKL-RANK in skeletal muscle – potential influences of RANKL inhibitors on sarcopenia. Top: domain structures of RANK, RANKL and OPG (inclusive of homodimerization activation stage) and general overview of RANK-RANKL-OPG signalling. Bottom: Summary of potential ways in which RANKL inhibitors may modulate skeletal muscle atrophy and subsequently sarcopenia. As well as inhibiting RANKL, OPG may modulate apoptosis pathways via interactions with TRAIL and may elicit responses in muscle via cooperation with surface proteins (e.g. integrins). TRAF may influence AKT dynamics in muscle [66, 67]. There may exist some other unknown modes of actions of OPG in skeletal muscle. Dashed lines represent potential RANK-RANKL independent interactions. RANKL may also interact with SFRP1 [68] and LGR4 [69] in skeletal muscle