Bone Signaling and RANKL

Question 1

What are molecules that stimulate bone resorption?

Answer 1

1) RANKL: RANKL (ligand) is secreted by osteoblasts and binds to the RANK receptor on osteoclast precursor and mature osteoclast cells
2) 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
3) interleukin 1 (IL-1): stimulates osteoclast differentiation and thus bone resorption
4) 1,25 dihydroxy vitamin D: stimulates RANKL expression
5) prostaglandin E2: activates adenylyl cyclase and stimulates resorption
6) IL-6 (myeloma)
7) MIP-1A (myeloma)

Question 2

What are substances that inhibit none resorption?

Answer 2

1) osteoprotegerin (OPG): decoy receptor produced by osteoblasts and stromal cells that binds to and sequesters RANKL; inhibits osteoclast differentiation, fusion, and activation
2) calcitonin: interacts directly with the osteoclast via cell-surface receptors
3) estrogen (via decrease in RANKL): stimulates bone production (anabolic) and prevents resorption; inhibits activation of adenylyl cyclase
4) transforming growth factor beta (via increase in OPG)
5) interleukin 10 (IL-10): suppresses osteoclasts

Question 3

What signaling pathway is responsible for the osteolysis found in pathologic lytic lesions?

Answer 3

RANKL-RANK; final common pathway regardless of pathologic lesion, macrophage activation in particle wear, or normal remodeling

Question 4

What cells are RANK and RANKL secreted by?

Answer 4

RANK: receptor found on osteoclasts; activation by RANK results in bone resorption
RANKL: secreted by osteoblasts, release stimulated by PTH