Updated: 11/15/2020

Bone Signaling & RANKL

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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 PTH 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  
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   
      • 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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