Beta 1 integrins and osteoclast function: involvement in collagen recognition and bone resorption.
The extracellular matrix of bone is composed mainly of type I collagen. In this report we studied the role and collagen-binding properties of osteoclast integrins (alpha v, alpha 2, beta 1, and beta 3). Cell adhesion assays with rat osteoclasts and affinity chromatography/SDS-PAGE analysis with purified human osteoclast membranes demonstrated adhesion of osteoclasts to native type I collagen in a divalent cation and Arg-Gly-Asp (RGD)-dependent way via alpha 2 beta 1 integrin, whereas osteoclast adhesion to denatured collagen predominantly involved alpha v beta 3. In receptor-binding assays, the involvement of human recombinant alpha v beta 3 in adhesion to denatured collagen was confirmed. Additionally, osteoclasts adhered to type I collagen fibers and to monomeric types II-V collagen with characteristics similar to those on native monomeric type I collagen. Osteoclastic bone resorption in vitro was inhibited (> 40%) in the presence of alpha 2 and beta 1 antibodies. Using scanning laser confocal microscopy, alpha v beta 3, alpha 2, and beta 1 integrin were detected within podosomes in nonresorbing osteoclasts and in the ruffled border area and basolateral membrane in resorbing osteoclasts, but not in the sealing zone of resorbing osteoclasts. These results demonstrate that alpha 2 beta 1, in addition to alpha v beta 3, has an important role in osteoclast function and acts as a receptor for native, but not denatured, collagen.
Department of Medicine and Therapeutics, University of Aberdeen, Scotland. m.helfrich@aberdeen.ac.uk
M H
MH
Helfrich
S A
SA
Nesbitt
P T
PT
Lakkakorpi
M J
MJ
Barnes
S C
SC
Bodary
G
G
Shankar
W T
WT
Mason
D L
DL
Mendrick
H K
HK
Väänänen
M A
MA
Horton
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001667:Binding, Competitive; D001862:Bone Resorption / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D002413:Cations, Divalent / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology*; D002846:Chromatography, Affinity; D003094:Collagen / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D007150:Immunohistochemistry; D016023:Integrins / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism; D009842:Oligopeptides / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D051381:Rats; D011971:Receptors, Immunologic / Q000378:metabolism
D000911:Antibodies, Monoclonal; D002413:Cations, Divalent; D016023:Integrins; D008565:Membrane Proteins; D009842:Oligopeptides; D010446:Peptide Fragments; D011971:Receptors, Immunologic; C047981:arginyl-glycyl-aspartic acid; D003094:Collagen