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Updated: Jun 16 2021

Bone Signaling & RANKL


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Images 2.jpg mechanism_moved.jpg
  • Introduction
    • Bone metabolism is a dynamic process that balances bone formation and bone resorption
      • central to this process is the RANK/RANKL/OPG pathway
      • bone formation
        • performed by stimulating osteoblasts and inhibiting osteoclasts
      • bone resorption
        • performed by active osteoclast
          • stimulated by RANKL in normal process
          • stimulated by PTHrP in pathologic process (metastatic disease)
  • Osteoblast Signaling in RANKL pathway
    • Osteoblasts produce
      • RANKL
        • binds RANK and stimulates osteoclastic bone resorption
      • osteoprotegerin (OPG)
        • inhibits osteoclast differentiation, fusion, and activation
        • decoy receptor produced by osteoblasts and stromal cells that binds to and sequesters RANKL
      • alkaline phosphatase
  • Osteoclast Inhibition
    • Osteoclast Inhibition decreases bone resorption
    • Molecules that inhibit bone resorption
      • osteoprotegerin (OPG)
      • calcitonin
        • interacts directly with the osteoclast via cell-surface receptors
      • estrogen (via decrease in RANKL)
        • stimulates bone production (anabolic) and prevents resorption
        • inhibits activation of adenylyl cyclase
      • transforming growth factor beta (TGF beta) (via increase in OPG)
      • interleukin 10 (IL-10)
        • suppresses osteoclasts
  • Osteoclast Activation
    • Osteoclast activation stimulates bone resorption
    • Molecules that stimulate bone resorption
        • RANKL (ligand) is secreted by osteoblasts and binds to the RANK receptor on osteoclast precursor and mature osteoclast cells
      • PTH
        • activation of its receptor stimulates adenylyl cyclase
        • binds to cell-surface receptors on osteoblasts to stimulate production of RANKL and M-CSF
      • interleukin 1 (IL-1)
        • stimulates osteoclast differentiation and thus bone resorption
      • 1,25 dihydroxy vitamin D
        • stimulates RANKL expression
      • prostaglandin E2
        • activates adenylyl cyclase and stimulates resorption
      • IL-6 (myeloma)
      • MIP-1A (myeloma)
  • Clinical Implications
    • Osteoporosis
      • can result from loss of function of the OPG gene, leading to constitutive activation of osteoclasts which results in uncontrolled bone resorption and ultimately leads to osteoporosis
    • Osteopetrosis
      • condition caused by a genetic defect resulting in absence of osteoclastic bone resorption
      • a mouse RANKL knockout model creates a osteopetrosis-like condition
    • Paget disease
      • felt to be caused by alterations in cytoplastmic binding to RANK or mutations in the OPG gene
    • Osteolytic bone metastasis
      • found to be mediated by the RANK and RANKL pathway
      • RANKL is produced directly by the cancer cells
      • blocking of RANKL by OPG results in decreased skeletal metastasis in animal models
      • bisphosphonates decrease skeletal events in cancer metastasis
    • Osteolysis following joint arthroplasty
      • polyethylene wear debris is phagocytized by macrophage leads to activation of the macrophage
      • additional macrophages are recruited with release of additional cytokines including RANKL
      • RANKL activates osteoclasts which leads to bone resorption around implants
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