Updated: 6/16/2021

Bone Signaling & RANKL

0%
Topic
Review Topic
0
0
0%
0%
Flashcards
26
N/A
N/A
Questions
16
0
0
0%
0%
Evidence
22
0
0
0%
0%
Videos / Pods
2
Topic
Images
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
      • 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
Flashcards (26)
Cards
1 of 26
Questions (16)
Question locked
Sorry, this question is for
PEAK Premium Subscribers only
Upgrade to PEAK
Question locked
Sorry, this question is for
PEAK Premium Subscribers only
Upgrade to PEAK
Question locked
Sorry, this question is for
PEAK Premium Subscribers only
Upgrade to PEAK
Question locked
Sorry, this question is for
PEAK Premium Subscribers only
Upgrade to PEAK
Question locked
Sorry, this question is for
PEAK Premium Subscribers only
Upgrade to PEAK

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

QID: 4719

It is secreted by osteoclasts

4%

(243/5527)

It increases bone resorption

4%

(197/5527)

Binds to prostoglandin E2 before stimulating osteoclasts

4%

(248/5527)

Osteoprotegerin knock-out mice develop osteopetrosis

6%

(352/5527)

Binds to and sequesters RANKL

80%

(4437/5527)

L 1 B

Select Answer to see Preferred Response

Question locked
Sorry, this question is for
PEAK Premium Subscribers only
Upgrade to PEAK
Question locked
Sorry, this question is for
PEAK Premium Subscribers only
Upgrade to PEAK

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

QID: 3474

Decreasing osteoclast activity by directly binding to receptor on the osteoclast

59%

(2274/3885)

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

19%

(743/3885)

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

5%

(206/3885)

Decreasing osteoclast activity by stimulating PTH to activate adenylyl cyclase

11%

(436/3885)

Increasing osteoclast activity by directly binding to receptor on the osteoclast

5%

(206/3885)

L 3 B

Select Answer to see Preferred Response

Question locked
Sorry, this question is for
PEAK Premium Subscribers only
Upgrade to PEAK

(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?

QID: 3139
FIGURES:

IL-4

3%

(73/2772)

RANK

77%

(2140/2772)

TNF-alpha

16%

(449/2772)

OPG

2%

(59/2772)

Sox-9

1%

(35/2772)

L 1 C

Select Answer to see Preferred Response

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

QID: 3326

SMADs

6%

(163/2621)

Parathyroid hormone (PTH)

50%

(1319/2621)

Insulin-like growth factor II (IGF-II)

11%

(300/2621)

Bone morphogenetic protein 2 (BMP-2)

19%

(509/2621)

Transforming growth factor-Beta (TGF-ß)

12%

(316/2621)

L 4 C

Select Answer to see Preferred Response

(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?

QID: 3088

Osteoclasts

14%

(419/2951)

Osteoblasts

83%

(2443/2951)

Integrins

1%

(30/2951)

T cells

1%

(27/2951)

Macrophages

1%

(30/2951)

L 5 C

Select Answer to see Preferred Response

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

QID: 871

Tumor necrosis factor-alpha (TNF-a)

67%

(1618/2398)

Osteoprotegerin

10%

(234/2398)

Calcitonin

12%

(295/2398)

Bisphosphonates

3%

(71/2398)

Denosumab

7%

(169/2398)

L 1 C

Select Answer to see Preferred Response

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

QID: 335

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

59%

(761/1288)

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

28%

(366/1288)

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

5%

(66/1288)

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

6%

(79/1288)

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

1%

(12/1288)

L 1 C

Select Answer to see Preferred Response

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

QID: 1251

Calcitonin

81%

(763/941)

RANK ligand

6%

(61/941)

Interleukin-6

1%

(13/941)

Parathyroid Hormone

9%

(86/941)

Dexamethasone

2%

(15/941)

L 1 C

Select Answer to see Preferred Response

Evidence (22)
VIDEOS & PODCASTS (6)
EXPERT COMMENTS (20)
Private Note