title: The role of subchondral bone remodeling in osteoarthritis: reduction of cartilage degeneration and prevention of osteophyte formation by alendronate in the rat anterior cruciate ligament transection model.
abstract: OBJECTIVE
  It has been suggested that subchondral bone remodeling plays a role in the progression of osteoarthritis (OA). To test this hypothesis, we characterized the changes in the rat anterior cruciate ligament transection (ACLT) model of OA and evaluated the effects of alendronate (ALN), a potent inhibitor of bone resorption, on cartilage degradation and on osteophyte formation.
  
  
  METHODS
  Male Sprague-Dawley rats underwent ACLT or sham operation of the right knee. Animals were then treated with ALN (0.03 and 0.24 microg/kg/week subcutaneously) and necropsied at 2 or 10 weeks postsurgery. OA changes were evaluated. Subchondral bone volume and osteophyte area were measured by histomorphometric analysis. Coimmunostaining for transforming growth factor beta (TGF beta), matrix metalloproteinase 9 (MMP-9), and MMP-13 was performed to investigate the effect of ALN on local activation of TGF beta.
  
  
  RESULTS
  ALN was chondroprotective at both dosages, as determined by histologic criteria and collagen degradation markers. ALN suppressed subchondral bone resorption, which was markedly increased 2 weeks postsurgery, and prevented the subsequent increase in bone formation 10 weeks postsurgery, in the untreated tibial plateau of ACLT joints. Furthermore, ALN reduced the incidence and area of osteophytes in a dose-dependent manner. ALN also inhibited vascular invasion into the calcified cartilage in rats with OA and blocked osteoclast recruitment to subchondral bone and osteophytes. ALN treatment reduced the local release of active TGF beta, possibly via inhibition of MMP-13 expression in articular cartilage and MMP-9 expression in subchondral bone.
  
  
  CONCLUSIONS
  Subchondral bone remodeling plays an important role in the pathogenesis of OA. ALN or other inhibitors of bone resorption could potentially be used as disease-modifying agents in the treatment of OA.
authors.affiliation: Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Hayami
authors.forename: Maureen
authors.initials: M
authors.lastname: Pickarski
authors.forename: Gregg A
authors.initials: GA
authors.lastname: Wesolowski
authors.forename: Julia
authors.initials: J
authors.lastname: McLane
authors.forename: Ashleigh
authors.initials: A
authors.lastname: Bone
authors.forename: James
authors.initials: J
authors.lastname: Destefano
authors.forename: Gideon A
authors.initials: GA
authors.lastname: Rodan
authors.forename: Le T
authors.initials: LT
authors.lastname: Duong
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D019386:Alendronate / Q000494:pharmacology*; D000818:Animals; D016118:Anterior Cruciate Ligament / Q000473:pathology* / Q000601:surgery; D016723:Bone Remodeling / Q000187:drug effects / Q000502:physiology*; D002114:Calcinosis / Q000473:pathology / Q000503:physiopathology; D002358:Cartilage, Articular / Q000098:blood supply / Q000473:pathology; D003094:Collagen / Q000652:urine; D024042:Collagen Type I; D024043:Collagen Type II / Q000652:urine; D004195:Disease Models, Animal; D018450:Disease Progression; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D064235:Matrilin Proteins; D020370:Osteoarthritis, Knee / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology*; D010010:Osteoclasts / Q000201:enzymology / Q000473:pathology; D010455:Peptides / Q000652:urine; D051381:Rats; D012598:Sclerosis; D012720:Severity of Illness Index; D000071681:Tartrate-Resistant Acid Phosphatase; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D024043:Collagen Type II; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D007527:Isoenzymes; D064235:Matrilin Proteins; D010455:Peptides; D016212:Transforming Growth Factor beta; C052929:collagen type I trimeric cross-linked peptide; D003094:Collagen; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; D019386:Alendronate