questions
9

Bone Signaling & RANKL

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Topic updated on 02/20/16 8:57pm
 
 
 
Introduction
  • Bone metabolism is a dynamic process that balances bone formation and bone resorption 
    • bone resorption 
      • performed by active osteoclast
        • stimulated by RANKL in normal process
        • stimulated by PTH in pathologic process (metastatic disease)
    • bone formation
      • performed by inhibiting osteoclasts and stimulating osteoblasts
        • OPG inhibits 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 (secreted by many cancer cells)
      • 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)
Osteoclast Inhibition
  • Osteoclast Inhibition decreases bone resorption
  • Molecules that inhibit bone resorption
    • osteoprotegerin (OPG) 
      • decoy receptor produced by osteoblasts and stromal cells that binds to and sequesters RANKL
      • inhibits osteoclast differentiation, fusion, and activation
    • 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 (via increase in OPG)
    • interleukin 10 (IL-10)
      • suppresses osteoclasts
Clinical Implications
  • Osteopetrosis 
    • condition caused by a genetic defect resulting in absence of osteoclastic bone resorption 
    • a mouse RANKL knockout model creates a osteopetrosis-like condition
  • Osteoyltic 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

 

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Qbank (9 Questions)

TAG
(OBQ13.84) Which of the following is true regarding osteoprotegerin (OPG)? Topic Review Topic

1. It is secreted by osteoclasts
2. It increases bone resorption
3. Binds to prostoglandin E2 before stimulating osteoclasts
4. Osteoprotegerin knock-out mice develop osteopetrosis
5. Binds to and sequesters RANKL

PREFERRED RESPONSE ▶
TAG
(OBQ11.51) Calcitonin plays a role in bone metabolism by which of the following mechanisms? Topic Review Topic

1. Decreasing osteoclast activity by directly binding to receptor on the osteoclast
2. Decreasing osteoclast activity by blocking the receptor activator for nuclear factor ligand (RANKL) pathway
3. Increasing osteoblast activity by receptor activator for nuclear factor ligand (RANKL) pathway
4. Decreasing osteoclast activity by stimulating PTH to activate adenylyl cyclase
5. Increasing osteoclast activity by directly binding to receptor on the osteoclast

PREFERRED RESPONSE ▶
TAG
(OBQ10.51) A 55-year-old female with a history of metastatic breast cancer develops shoulder pain without any trauma. Which of the following is involved with the findings shown in Figures A and B? Topic Review Topic
FIGURES: A   B        

1. IL-4
2. RANK
3. TNF-alpha
4. OPG
5. Sox-9

PREFERRED RESPONSE ▶
TAG
(OBQ10.227) Which of the following bone modulators primarily utilizes adenylyl cyclase as a mediator for its cellular signaling within osteocytes? Topic Review Topic

1. SMADs
2. Parathyroid hormone (PTH)
3. Insulin-like growth factor II (IGF-II)
4. Bone morphogenetic protein 2 (BMP-2)
5. Transforming growth factor-Beta (TGF-ß)

PREFERRED RESPONSE ▶
TAG
(OBQ09.275) Receptor activator of nuclear-factor kappa-B ligand (RANKL) is an important regulator of bone resorption. Which of the following cells is the MAJOR source of RANKL in bone remodelling? Topic Review Topic

1. Osteoclasts
2. Osteoblasts
3. Integrins
4. T cells
5. Macrophages

PREFERRED RESPONSE ▶
TAG
(OBQ07.210) All of the following substances inhibit osteoclast activity, EXCEPT? Topic Review Topic

1. Tumor necrosis factor-alpha (TNF-a)
2. Osteoprotegerin
3. Calcitonin
4. Bisphosphonates
5. Denosumab

PREFERRED RESPONSE ▶
TAG
(OBQ06.149) Which of the following best describes the mechanism by which osteoprotegerin (OPG) plays a role in RANKL-mediated osteoclast bone resorption? Topic Review Topic

1. inhibits RANKL-mediated osteoclast bone resorption by directly binding to RANKL
2. inhibits RANKL-mediated osteoclast bone resorption by directly binding to the RANK receptor on osteoclasts
3. stimulates RANKL-mediated osteoclast bone resorption by directly binding to RANKL
4. stimulates RANKL-mediated osteoclast bone resorption by directly binding to the RANK receptor on osteoclasts
5. stimulates RANKL-mediated osteoclast bone resorption by directly binding to PTH

PREFERRED RESPONSE ▶
TAG
(OBQ04.146) Which of the following mediators reduces bone resorption? Topic Review Topic

1. Calcitonin
2. RANK ligand
3. Interleukin-6
4. Parathyroid Hormone
5. Dexamethasone

PREFERRED RESPONSE ▶
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Bone Remodeling and regulation including osteoprotegrin, RANK, RANK-ligand
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