title: Osteopontin deficiency produces osteoclast dysfunction due to reduced CD44 surface expression.
abstract: Osteopontin (OPN) was expressed in murine wild-type osteoclasts, localized to the basolateral, clear zone, and ruffled border membranes, and deposited in the resorption pits during bone resorption. The lack of OPN secretion into the resorption bay of avian osteoclasts may be a component of their functional resorption deficiency in vitro. Osteoclasts deficient in OPN were hypomotile and exhibited decreased capacity for bone resorption in vitro. OPN stimulated CD44 expression on the osteoclast surface, and CD44 was shown to be required for osteoclast motility and bone resorption. Exogenous addition of OPN to OPN-/- osteoclasts increased the surface expression of CD44, and it rescued osteoclast motility due to activation of the alpha(v)beta(3) integrin. Exogenous OPN only partially restored bone resorption because addition of OPN failed to produce OPN secretion into resorption bays as seen in wild-type osteoclasts. As expected with these in vitro findings of osteoclast dysfunction, a bone phenotype, heretofore unappreciated, was characterized in OPN-deficient mice. Delayed bone resorption in metaphyseal trabeculae and diminished eroded perimeters despite an increase in osteoclast number were observed in histomorphometric measurements of tibiae isolated from OPN-deficient mice. The histomorphometric findings correlated with an increase in bone rigidity and moment of inertia revealed by load-to-failure testing of femurs. These findings demonstrate the role of OPN in osteoclast function and the requirement for OPN as an osteoclast autocrine factor during bone remodeling.
authors.affiliation: Department of Oral/Craniofacial Biological Sciences, University of Maryland, Baltimore, Maryland 21201, USA. mac001@dental.umaryland.edu
authors.forename: M A
authors.initials: MA
authors.lastname: Chellaiah
authors.forename: N
authors.initials: N
authors.lastname: Kizer
authors.forename: R
authors.initials: R
authors.lastname: Biswas
authors.forename: U
authors.initials: U
authors.lastname: Alvarez
authors.forename: J
authors.initials: J
authors.lastname: Strauss-Schoenberger
authors.forename: L
authors.initials: L
authors.lastname: Rifas
authors.forename: S R
authors.initials: SR
authors.lastname: Rittling
authors.forename: D T
authors.initials: DT
authors.lastname: Denhardt
authors.forename: K A
authors.initials: KA
authors.lastname: Hruska
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D018960:Hyaluronan Receptors / Q000276:immunology / Q000378:metabolism*; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D051379:Mice; D010010:Osteoclasts / Q000378:metabolism*; D053495:Osteopontin; D012795:Sialoglycoproteins / Q000172:deficiency* / Q000276:immunology; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D000906:Antibodies; D018960:Hyaluronan Receptors; D039302:Integrin alphaVbeta3; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; D053495:Osteopontin; D020742:rhoA GTP-Binding Protein