title: Targeting bone alleviates osteoarthritis in osteopenic mice and modulates cartilage catabolism.
abstract: OBJECTIVE
  Subchondral bone modifications occur early in the development of osteoarthritis (OA). The level of bone resorption might impact cartilage remodeling. We therefore assessed the in vivo and in vitro effects of targeting bone resorption in OA and cartilage metabolism.
  
  
  METHODS
  OA was induced by meniscectomy (MNX) in ovariectomized osteopenic mice (OP) treated with estradiol (E2), pamidronate (PAM), or phosphate buffered saline (PBS) for 6 weeks. We assessed the subchondral bone and cartilage structure and the expression of cartilage matrix proteases. To assess the involvement of bone soluble factors in cartilage metabolism, supernatant of human bone explants pre-treated with E2 or PAM were transferred to cartilage explants to assess proteoglycan release and aggrecan cleavage. OPG/RANKL mRNA expression was assessed in bone explants by real-time quantitative PCR. The role of osteoprotegerin (OPG) in the bone-cartilage crosstalk was tested using an OPG neutralizing antibody.
  
  
  RESULTS
  Bone mineral density of OP mice and osteoclast number were restored by E2 and PAM (p<0.05). In OP mice, E2 and PAM decreased ADAMTS-4 and -5 expression, while only PAM markedly reduced OA compared to PBS (2.0±0.63 vs 5.2±0.95; p<0.05). OPG/RANKL mRNA was increased in human bone explants treated with both drugs (2.2-3.7-fold). Moreover, supernatants from bone explants cultured with E2 or PAM reduced aggrecan cleavage and cartilage proteoglycan release (73±8.0% and 80±22% of control, respectively, p<0.05). This effect was reversed with osteoprotegerin blockade.
  
  
  CONCLUSIONS
  The inhibition of bone resorption by pamidronate in osteopenic mice alleviates the histological OA score with a reduction in the expression of aggrecanases. Bone soluble factors, such as osteoprotegerin, impact the cartilage response to catabolic factors. This study further highlights the importance of subchondral bone in the regulation of joint cartilage damage in OA.
authors.affiliation: INSERM U606, Centre Viggo Petersen and Université Paris-Diderot Paris 7, Hôpital Lariboisière, Paris, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Funck-Brentano
authors.forename: Hilène
authors.initials: H
authors.lastname: Lin
authors.forename: Eric
authors.initials: E
authors.lastname: Hay
authors.forename: Marie-Dominique
authors.initials: MD
authors.lastname: Ah Kioon
authors.forename: Corinne
authors.initials: C
authors.lastname: Schiltz
authors.forename: Didier
authors.initials: D
authors.lastname: Hannouche
authors.forename: Rémy
authors.initials: R
authors.lastname: Nizard
authors.forename: Frédéric
authors.initials: F
authors.lastname: Lioté
authors.forename: Philippe
authors.initials: P
authors.lastname: Orcel
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: de Vernejoul
authors.forename: Martine Esther
authors.initials: ME
authors.lastname: Cohen-Solal
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000071116:ADAMTS5 Protein; D000818:Animals; D001851:Bone Diseases, Metabolic / Q000150:complications / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D001862:Bone Resorption / Q000150:complications / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002356:Cartilage / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D004164:Diphosphonates / Q000494:pharmacology / Q000627:therapeutic use; D004958:Estradiol / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008592:Menisci, Tibial / Q000473:pathology / Q000601:surgery; D051379:Mice; D008810:Mice, Inbred C57BL; D010003:Osteoarthritis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D053244:Osteoprotegerin / Q000378:metabolism; D000077268:Pamidronate; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D004164:Diphosphonates; D053244:Osteoprotegerin; D020011:Protective Agents; D004958:Estradiol; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C498489:Adamts5 protein, mouse; D000077268:Pamidronate