Which pathway regulates bone metabolism through osteoclast signaling?
The RANKL/RANK/OPG signaling pathway involves members of the TNF superfamily and is a critical pathway for the regulation of osteoclast activation and bone remodeling.
RANKL is a cell membrane-bound ligand (can also be secreted) on osteoblasts, activated T cells, and other cells. It binds RANK on osteoclast precursors, which causes the osteoclast to differentiate and become activated. In most cases, RANKL is also assisted by macrophage colony-stimulated factor (M-CSF) as a cofactor for osteoclast differentiation. OPG is a soluble, regulatory cytokine secreted by osteoblasts that competitively binds RANKL and prevents its binding to RANK, thus inhibiting osteoclastogenesis. Expression of RANKL on osteoblasts is stimulated through vitamin D receptor (1,25 OH vitamin D 3 ), protein kinase A (prostaglandin E 2 [PGE 2 ], parathyroid hormone), and gp 130 (IL-11). Cytokines (IL-1, IL-7, IL-17, TNF-α, M-CSF) and glucocorticoids also upregulate RANKL expression while downregulating OPG production. The periarticular osteoporosis and erosions seen on radiographs of individuals with inflammatory arthritis may be through local production of PGE 2 and interleukins (TNF-α, IL-1), causing upregulation of RANKL on osteoblasts and T cells leading to osteoclast activation. Conversely, blocking RANKL (i.e., denosumab) is a therapy for osteoporosis. Genetic disorders due to mutations in this signaling pathway have been reported. Activating mutations of RANK cause diseases characterized by bone deformities, dental defects, and deafness. An inactivating mutation of OPG is associated with juvenile Paget’s disease.