Please confirm topic selection

Are you sure you want to trigger topic in your Anconeus AI algorithm?

Please confirm action

You are done for today with this topic.

Would you like to start learning session with this topic items scheduled for future?

Updated: Jun 16 2021

Bone Signaling & RANKL

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
1 of 26
1 of 16
Private Note

Attach Treatment Poll
Treatment poll is required to gain more useful feedback from members.
Please enter Question Text
Please enter at least 2 unique options
Please enter at least 2 unique options
Please enter at least 2 unique options