title: Molecular changes in articular cartilage and subchondral bone in the rat anterior cruciate ligament transection and meniscectomized models of osteoarthritis.
abstract: BACKGROUND
  Osteoarthritis (OA) is a debilitating, progressive joint disease.
  
  
  METHODS
  Similar to the disease progression in humans, sequential events of early cartilage degradation, subchondral osteopenia followed by sclerosis, and late osteophyte formation were demonstrated in the anterior cruciate ligament transection (ACLT) or ACLT with partial medial meniscectomy (ACLT + MMx) rat OA models. We describe a reliable and consistent method to examine the time dependent changes in the gene expression profiles in articular cartilage and subchondral bone.
  
  
  RESULTS
  Local regulation of matrix degradation markers was demonstrated by a significant increase in mRNA levels of aggrecanase-1 and MMP-13 as early as the first week post-surgery, and expression remained elevated throughout the 10 week study. Immunohistochemistry confirmed MMP-13 expression in differentiated chondrocytes and synovial fibroblasts at week-2 and cells within osteophytes at week-10 in the surgically-modified-joints. Concomitant increases in chondrocyte differentiation markers, Col IIA and Sox 9, and vascular invasion markers, VEGF and CD31, peaked around week-2 to -4, and returned to Sham levels at later time points in both models. Indeed, VEGF-positive cells were found in the deep articular chondrocytes adjacent to subchondral bone. Osteoclastic bone resorption markers, cathepsin K and TRAP, were also elevated at week-2. Confirming bone resorption is an early local event in OA progression, cathepsin K positive osteoclasts were found invading the articular cartilage from the subchondral region at week 2. This was followed by late disease events, including subchondral sclerosis and osteophyte formation, as demonstrated by the upregulation of the osteoanabolic markers runx2 and osterix, toward week-4 to 6 post-surgery.
  
  
  CONCLUSIONS
  In summary, this study demonstrated the temporal and cohesive gene expression changes in articular cartilage and subchondral bone using known markers of OA progression. The findings here support genome-wide profiling efforts to elucidate the sequential and complex regulation of the disease.
authors.affiliation: Merck Sharpe & Dohme Corp,, Bone Biology Group, West Point, PA 19486, USA.
authors.forename: Maureen
authors.initials: M
authors.lastname: Pickarski
authors.forename: Tadashi
authors.initials: T
authors.lastname: Hayami
authors.forename: Ya
authors.initials: Y
authors.lastname: Zhuo
authors.forename: Le T
authors.initials: LT
authors.lastname: Duong
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000071121:ADAMTS4 Protein; D000818:Animals; D016118:Anterior Cruciate Ligament / Q000378:metabolism* / Q000601:surgery; D015415:Biomarkers / Q000378:metabolism; D016723:Bone Remodeling / Q000502:physiology; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D015870:Gene Expression; D020869:Gene Expression Profiling; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism; D008592:Menisci, Tibial / Q000378:metabolism / Q000601:surgery; D020370:Osteoarthritis, Knee / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D054850:Osteophyte / Q000378:metabolism / Q000473:pathology; D011348:Procollagen N-Endopeptidase / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology; D013977:Tibia / Q000378:metabolism / Q000473:pathology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D015415:Biomarkers; D050659:Core Binding Factor Alpha 1 Subunit; D012333:RNA, Messenger; C493717:Runx2 protein, rat; C495181:Sp7 protein, rat; D014157:Transcription Factors; D051722:ADAM Proteins; D053509:Matrix Metalloproteinase 13; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein