Updated: 10/10/2016

Bone Signaling & RANKL

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https://upload.orthobullets.com/topic/9010/images/rank 2.jpg
https://upload.orthobullets.com/topic/9010/images/RANKL mechanism_moved.jpg
 
 
 
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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Questions (12)
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(OBQ13.84) Which of the following is true regarding osteoprotegerin (OPG)? Review Topic

QID: 4719
1

It is secreted by osteoclasts

4%

(191/4322)

2

It increases bone resorption

4%

(153/4322)

3

Binds to prostoglandin E2 before stimulating osteoclasts

4%

(193/4322)

4

Osteoprotegerin knock-out mice develop osteopetrosis

7%

(283/4322)

5

Binds to and sequesters RANKL

80%

(3463/4322)

ML 2

Select Answer to see Preferred Response

PREFERRED RESPONSE 5

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

QID: 1251
1

Calcitonin

83%

(309/371)

2

RANK ligand

6%

(24/371)

3

Interleukin-6

1%

(4/371)

4

Parathyroid Hormone

8%

(28/371)

5

Dexamethasone

1%

(5/371)

ML 1

Select Answer to see Preferred Response

PREFERRED RESPONSE 1

(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? Review Topic

QID: 3088
1

Osteoclasts

12%

(268/2193)

2

Osteoblasts

85%

(1868/2193)

3

Integrins

1%

(25/2193)

4

T cells

1%

(15/2193)

5

Macrophages

1%

(15/2193)

ML 5

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PREFERRED RESPONSE 2

(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? Review Topic

QID: 3139
FIGURES:
1

IL-4

3%

(60/2284)

2

RANK

78%

(1789/2284)

3

TNF-alpha

16%

(357/2284)

4

OPG

2%

(44/2284)

5

Sox-9

1%

(22/2284)

ML 2

Select Answer to see Preferred Response

PREFERRED RESPONSE 2

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

QID: 871
1

Tumor necrosis factor-alpha (TNF-a)

67%

(965/1434)

2

Osteoprotegerin

9%

(133/1434)

3

Calcitonin

12%

(167/1434)

4

Bisphosphonates

3%

(44/1434)

5

Denosumab

8%

(117/1434)

ML 2

Select Answer to see Preferred Response

PREFERRED RESPONSE 1

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

QID: 3326
1

SMADs

7%

(130/1890)

2

Parathyroid hormone (PTH)

50%

(947/1890)

3

Insulin-like growth factor II (IGF-II)

12%

(219/1890)

4

Bone morphogenetic protein 2 (BMP-2)

18%

(347/1890)

5

Transforming growth factor-Beta (TGF-ß)

13%

(237/1890)

ML 4

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PREFERRED RESPONSE 2

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

QID: 335
1

inhibits RANKL-mediated osteoclast bone resorption by directly binding to RANKL

57%

(402/705)

2

inhibits RANKL-mediated osteoclast bone resorption by directly binding to the RANK receptor on osteoclasts

31%

(219/705)

3

stimulates RANKL-mediated osteoclast bone resorption by directly binding to RANKL

5%

(37/705)

4

stimulates RANKL-mediated osteoclast bone resorption by directly binding to the RANK receptor on osteoclasts

5%

(38/705)

5

stimulates RANKL-mediated osteoclast bone resorption by directly binding to PTH

1%

(6/705)

ML 3

Select Answer to see Preferred Response

PREFERRED RESPONSE 1

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

QID: 3474
1

Decreasing osteoclast activity by directly binding to receptor on the osteoclast

61%

(1613/2647)

2

Decreasing osteoclast activity by blocking the receptor activator for nuclear factor ligand (RANKL) pathway

18%

(484/2647)

3

Increasing osteoblast activity by receptor activator for nuclear factor ligand (RANKL) pathway

5%

(130/2647)

4

Decreasing osteoclast activity by stimulating PTH to activate adenylyl cyclase

10%

(276/2647)

5

Increasing osteoclast activity by directly binding to receptor on the osteoclast

5%

(132/2647)

ML 3

Select Answer to see Preferred Response

PREFERRED RESPONSE 1
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