Necessity of inositol (1,4,5)-trisphosphate receptor 1 and mu-calpain in NO-induced osteoclast motility.
In skeletal remodeling, osteoclasts degrade bone, detach and move to new locations. Mechanical stretch and estrogen regulate osteoclast motility via nitric oxide (NO). We have found previously that NO stimulates guanylyl cyclase, activating the cGMP-dependent protein kinase 1 (PKG1), reversibly terminating osteoclast matrix degradation and attachment, and initiating motility. The PKG1 substrate vasodilator-stimulated protein (VASP), a membrane-attachment-related protein found in complexes with the integrin alphavbeta3 in adherent osteoclasts, was also required for motility. Here, we studied downstream mechanisms by which the NO-dependent pathway mediates osteoclast relocation. We found that NO-stimulated motility is dependent on activation of the Ca(2+)-activated proteinase mu-calpain. RNA interference (RNAi) showed that NO-dependent activation of mu-calpain also requires PKG1 and VASP. Inhibition of Src kinases, which are involved in the regulation of adhesion complexes, also abolished NO-stimulated calpain activity. Pharmacological inhibition and RNAi showed that calpain activation in this process is mediated by the inositol (1,4,5)-trisphosphate receptor 1 [Ins(1,4,5)P(3)R1] Ca(2+) channel. We conclude that NO-induced motility in osteoclasts requires regulated Ca(2+) release, which activates mu-calpain. This occurs via the Ins(1,4,5)P(3)R1.
Yaroslavskiy
Beatrice B
BB
Department of Pathology, University of Pittsburgh, Veteran's Affairs Medical Center, Pittsburgh, PA 15243, USA.
Sharrow
Allison C
AC
Wells
Alan
A
Robinson
Lisa J
LJ
Blair
Harry C
HC
D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects*; D006152:Cyclic GMP / Q000494:pharmacology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D008840:Microfilament Proteins / Q000378:metabolism; D009569:Nitric Oxide / Q000494:pharmacology*; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D000098662:Vasodilator-Stimulated Phosphoprotein
D015815:Cell Adhesion Molecules; D004791:Enzyme Inhibitors; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008840:Microfilament Proteins; D010750:Phosphoproteins; D000098662:Vasodilator-Stimulated Phosphoprotein; D009569:Nitric Oxide; D016392:Proto-Oncogene Proteins pp60(c-src); D051057:Proto-Oncogene Proteins c-akt; D017869:Cyclic GMP-Dependent Protein Kinases; D002154:Calpain; C449002:mu-calpain; D006152:Cyclic GMP; D002118:Calcium
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