It is a complex that results from the interaction between a 317 aa peptide, a member of the tumor necrosis factor (TNF) superfamily and expressed on osteoblast progenitor cells (RANK), and its receptor (RANKL) expressed on osteoclast precursors (Fig. 1). RANKL/RANK in-interaction results in the activation, differentiation, and fusion of osteoclast precursor hematopoietic cells and subsequent activation of the bone resorption process.
Fig1. The RANK/RANKL/OPG system and bone remodeling. (Copyright EDISES 2021. Reproduced with permission)
The progress of this process is inhibited by osteoprotegerin (OPG), a glycoprotein acting as a RANKL receptor antagonist, which inhibits the final differentiation and activation of osteoclasts, thus regulating the resorption process. This mechanism and, in particular, the demonstration that OPG is produced mainly by osteoblast progenitor cells rep resent further evidence of the close functional link between the mechanisms of neoformation and resorption. Interestingly, unlike all biochemical markers of bone remodeling characterized by a known circadian rhythm, OPG and RANKL present a constant circulating concentration. This characteristic could be attributed either to their long half-life as well as to a substantially stable release of these molecules from the bone tissue or to the fact that the measurement of the circulating pool could mask variations in tissue-specific isoforms. Based on these data, it can be hypothesized that the nocturnal increase in osteoclast activity is mediated by a mechanism independent of the RANKL/OPG ratio. The measurement of the concentration of these molecules has so far proved to be uninformative not only due to the presence in the circulation of both soluble and membrane-bound forms but also because of the analytical problems of the measurement methods and interpretation and expression of the results.
However, the critical role of the molecules described has led to the development of specific inhibitors of RANKL, some of which are used for therapeutic purposes, demonstrating real effectiveness in inhibiting the phase of skeletal resorption.
