Bone Signaling Pathways (Wnt, RANK-RANKL-OPG, BMP/TGF-β, Hedgehog, Notch)

Osteoclasts are formed and activated by RANKL (Receptor Activator of Nuclear factor-κB Ligand), produced by osteoblast-lineage cells and osteocytes (and, in disease, by activated T cells). RANKL binds its receptor RANK on osteoclast precursors, which - together with M-CSF - drives their fusion, differentiation and bone-resorbing activity. The body's restraint is osteoprotegerin (OPG), a soluble decoy receptor secreted by osteoblasts that binds RANKL and prevents it reaching RANK. The RANKL:OPG ratio therefore sets the level of bone resorption: a high ratio means more osteoclasts and bone loss; a low ratio protects bone.

• Denosumab = a human monoclonal antibody to RANKL (mimics OPG) - a potent antiresorptive for osteoporosis and skeletal metastases.
• Oestrogen deficiency raises the RANKL:OPG ratio and increases IL-1/IL-6/TNF, accelerating postmenopausal bone loss.
• Many pathologies of bone loss (myeloma, inflammatory arthritis, metastasis) converge on up-regulated RANKL.

In the canonical Wnt pathway, a Wnt ligand binds the Frizzled (FZD) receptor together with the co-receptor LRP5/6. This inhibits the destruction complex so that β-catenin is stabilised, enters the nucleus and partners with TCF/LEF to switch on osteoblastogenic genes - increasing osteoblast number and bone formation (and indirectly raising OPG, lowering resorption). The pathway is held in check by inhibitors: sclerostin (made by osteocytes from the SOST gene) and Dkk1, which bind LRP4/5/6 and switch Wnt off.

• LRP5 gain-of-function -> high bone mass phenotype; LRP5 loss-of-function -> osteoporosis-pseudoglioma syndrome (low bone mass). These human experiments proved Wnt's central role.
• ROMOSOZUMAB is a monoclonal antibody against sclerostin - it releases the Wnt brake and is a potent anabolic osteoporosis drug (dual effect: increases formation and decreases resorption).
• Mechanical loading lowers sclerostin (bone responds to load by building) - the molecular basis of Wolff's law.

These pathways do not act in isolation. Resorption and formation are coupled: osteoclastic resorption releases TGF-β and IGF-1 stored in bone matrix, which recruit osteoblasts to refill the cavity, while osteoblast-lineage cells reciprocally control osteoclasts through RANKL/OPG. Anabolic and antiresorptive drugs work by tipping this coupled system - which is why, for example, denosumab withdrawal produces a rebound in resorption.