title: ADAM12-S stimulates bone growth in transgenic mice by modulating chondrocyte proliferation and maturation.
abstract: ADAM12-S transgenic mice exhibit a pronounced increase in the length of bones, such as femur, tibia, and vertebrae. The effect of ADAM12-S on longitudinal bone growth involves the modulation of chondrocyte proliferation and maturation, likely through proteolytic activities and altered cell-extracellular matrix interactions in the growth plate.
  
  
  BACKGROUND
  The disintegrin and metalloprotease ADAM12 is expressed in both osteoblasts and osteoclasts, suggesting a regulatory role of ADAM12 in bone. However, thus far, no in vivo function of ADAM12 in the skeleton has been reported.
  
  
  METHODS
  Transgenic mice expressing the secreted form of human ADAM12, ADAM12-S, or a truncated metalloprotease-deficient form of ADAM12-S in the circulation were used to study the effects of ADAM12 on the skeleton. In addition, murine chondrocyte cultures were used to study the effect of ADAM12-S on cell-extracellular matrix interactions.
  
  
  RESULTS
  ADAM12-S transgenic mice exhibit increased longitudinal bone growth. The increased bone length is progressive and age dependent, with a maximum increase of 17% seen in the femur from 6-month-old transgenic mice. The effect is gene dose dependent, being more pronounced in mice expressing higher levels of the transgene than in a lower-expressing line. Histological analysis revealed no alterations in the growth plate organization, but mean growth plate width was increased. Both the cellular incorporation of bromodeoxyuridine and the width of the collagen type X-positive hypertrophic zone were increased in the growth plate of ADAM12-S transgenic mice. Importantly, mice expressing a truncated form of ADAM12-S that lacked the pro- and metalloprotease domains showed no alterations in bone length, suggesting that protease activity is required for the ADAM12-S effect. In vitro studies showed that ADAM12-S inhibits chondrocyte adhesion to fibronectin and collagen type II.
  
  
  CONCLUSIONS
  ADAM12-S stimulates bone growth in mice by modulating chondrocyte proliferation and maturation through mechanisms probably involving both metalloprotease and adhesion activities.
authors.affiliation: Institute of Molecular Pathology, University of Copenhagen, Copenhagen, Denmark. kveiborg@pai.ku.dk
authors.forename: Marie
authors.initials: M
authors.lastname: Kveiborg
authors.forename: Reidar
authors.initials: R
authors.lastname: Albrechtsen
authors.forename: Lise
authors.initials: L
authors.lastname: Rudkjaer
authors.forename: Guanmei
authors.initials: G
authors.lastname: Wen
authors.forename: Karen
authors.initials: K
authors.lastname: Damgaard-Pedersen
authors.forename: Ulla M
authors.initials: UM
authors.lastname: Wewer
mesh_terms: D051722:ADAM Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D000072199:ADAM12 Protein; D000818:Animals; D001846:Bone Development / Q000235:genetics; D001842:Bone and Bones / Q000033:anatomy & histology* / Q000737:chemistry / Q000378:metabolism; D002448:Cell Adhesion; D002454:Cell Differentiation; D049109:Cell Proliferation; D019902:Chondrocytes / Q000166:cytology* / Q000502:physiology; D006801:Humans; D016023:Integrins / Q000032:analysis / Q000378:metabolism; D008565:Membrane Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D017384:Sequence Deletion
chemical_list: D016023:Integrins; D008565:Membrane Proteins; D051722:ADAM Proteins; D000072199:ADAM12 Protein; C000606480:ADAM12 protein, human