Osteoclasts and Bone Resorption

Osteoclast

-Large cells, many nucleus -lineage with blood cell (macrophages) -precursors circulate blood/marrow -mature --> formed by fusion of precursors -resorb bone, sealed compartments, secrete acids to degrade bone (ruffled border) -undergo apoptosis after resorbing bone

Osteoclastogenesis

Bone marrow precursor --> release M-CSF --> preosteoclast preosteoclast--> release M-CSF, RANKL --> fused polykaryon, but if OPG then stay poc fused polykaryon --> RANKL --> active oc (OPG inhibit)

Osteoclast markers

F4/80- (macrophage marker) TRAP+ (tartrate-resistant acid phosphatase) CTR+ (calcitonin receptor) beta3+ (beta 3 integrin) CATK (Cathepsin K)

Mechanism of osteoclastic bone resorption

H+, HCO3-, Cl- gradient (influx of H+ and Cl- into sealed compartment) -alpha5beta3 protein -CATK -sealed compartment has low pH to resorb bone tissues -TGN (trans Golgi)

Vicious cell-cell interaction cycle in bone marrow

Osteoclasts stimulate factors to increase cancer proliferation Cancer cells stimulate factors to increase osteoclast proliferation Can slow bone resorption to slow cancer.. never fully stop it

How are mature osteoclasts formed? (what signals)

RANK receptors from osteoclast precursors activated by RANKL, *secreted by osteoblasts* *Osteoprotegerin* (OPG) in marrow, also help regulate osteoclast activation

Osteoprotegrin (OPG)

decoy receptor that prevents RANKL from binding RANK and inhibits osteoclast formation, function, and survival

RANKL

essential mediator of osteoclast formation, function, survival

Where does bone resorption occur?

inside the actin ring

Osteopetrotic mice

op/op mouse has defect in gene that produces M-CSF (macrophage colony stimulating factor) CANNOT STIMULATE OSTEOCLAST (no resorption)

If RANKL overwhelms OPG?

resorption can become excessive, lead to osteoporosis