title: Mice lacking the integrin beta5 subunit have accelerated osteoclast maturation and increased activity in the estrogen-deficient state.
abstract: Integrin alphavbeta5 is expressed on osteoclast precursors and is capable of recognizing the same amino acid motif as alphavbeta3. Three-month-old beta5(-/-) female OVX mice had increased osteoclastogenesis ex vivo, and microCT assessment of trabecular bone volume was 53% lower than WT-OVX animals. These preliminary data suggest alphavbeta5 integrin's presence on osteoclast precursors may inhibit of osteoclast formation.
  
  
  BACKGROUND
  Osteoclasts are unique resorptive skeletal cells, capable of degrading bone on contact to the juxtaposed matrix. Integrin alphavbeta5 is expressed on osteoclast precursors, structurally similar to alphavbeta3, and capable of recognizing the same amino acid motif. Given the structural relationship and reciprocal regulation of alphavbeta3 and alphavbeta5, the purpose of this study was to evaluate how alphavbeta5 might contribute to osteoclast maturation and activity.
  
  
  METHODS
  Three-month-old wildtype (WT) and beta5(-/-) female mice had ovariectomy (OVX) or sham operations. The osteoclastogenic capacity of marrow-derived precursors, the kinetic, the circulating, and structural parameters of bone remodeling, was determined after 6 weeks of paired feeding.
  
  
  CONCLUSIONS
  OVX increased osteoclastogenesis ex vivo and in vivo. Osteoclast formation and prolonged pre-osteoclast survival were substantially enhanced in cultures containing beta5(-/-) cells whether obtained from sham-operated or OVX mice. Expression of cathepsin K, beta3 integrin subunit, and calcitonin receptor were accelerated in cultured beta5(-/-)osteoclasts. beta5(-/-) osteoclasts from OVX animals showed a 3-fold enhancement of net resorptive activity, with quantitative muCT showing trabecular bone volume loss after OVX 53% greater in beta5(-/-) OVX compared with similarly treated WT OVX mice (p < 0.05). alpha5beta3 seems to be an inhibitor of osteoclast formation, in contrast to alphavbeta3. In addition, loss of alphavbeta5 seems to accelerate osteoclast formation in the OVX model. Further examination of alphavbeta5 signaling pathways may enhance our understanding of the activation of bone resorption.
authors.affiliation: Department of Medicine, University of California at San Francisco, San Francisco, California 94143, USA. nelane@itsa.ucsf.edu
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Lane
authors.forename: Wei
authors.initials: W
authors.lastname: Yao
authors.forename: Mary C
authors.initials: MC
authors.lastname: Nakamura
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Humphrey
authors.forename: Donald
authors.initials: D
authors.lastname: Kimmel
authors.forename: Xiaozhu
authors.initials: X
authors.lastname: Huang
authors.forename: Dean
authors.initials: D
authors.lastname: Sheppard
authors.forename: F Patrick
authors.initials: FP
authors.lastname: Ross
authors.forename: Steven L
authors.initials: SL
authors.lastname: Teitelbaum
mesh_terms: D000818:Animals; D001862:Bone Resorption; D056657:Cathepsin K; D002403:Cathepsins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D004967:Estrogens / Q000172:deficiency*; D005260:Female; D015870:Gene Expression; D039302:Integrin alphaVbeta3 / Q000235:genetics / Q000378:metabolism; D039641:Integrin beta Chains / Q000235:genetics / Q000502:physiology*; D039661:Integrin beta3 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D010010:Osteoclasts / Q000166:cytology* / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018003:Receptors, Calcitonin / Q000235:genetics / Q000378:metabolism
chemical_list: D004967:Estrogens; D039302:Integrin alphaVbeta3; D039641:Integrin beta Chains; D039661:Integrin beta3; D012333:RNA, Messenger; D018003:Receptors, Calcitonin; C084344:integrin beta5; D002403:Cathepsins; D056657:Cathepsin K; C534132:Ctsk protein, mouse