title: Disease progression and phasic changes in gene expression in a mouse model of osteoarthritis.
abstract: Osteoarthritis (OA) is the most common form of arthritis and has multiple risk factors including joint injury. The purpose of this study was to characterize the histologic development of OA in a mouse model where OA is induced by destabilization of the medial meniscus (DMM model) and to identify genes regulated during different stages of the disease, using RNA isolated from the joint "organ" and analyzed using microarrays. Histologic changes seen in OA, including articular cartilage lesions and osteophytes, were present in the medial tibial plateaus of the DMM knees beginning at the earliest (2 week) time point and became progressively more severe by 16 weeks. 427 probe sets (371 genes) from the microarrays passed consistency and significance filters. There was an initial up-regulation at 2 and 4 weeks of genes involved in morphogenesis, differentiation, and development, including growth factor and matrix genes, as well as transcription factors including Atf2, Creb3l1, and Erg. Most genes were off or down-regulated at 8 weeks with the most highly down-regulated genes involved in cell division and the cytoskeleton. Gene expression increased at 16 weeks, in particular extracellular matrix genes including Prelp, Col3a1 and fibromodulin. Immunostaining revealed the presence of these three proteins in cartilage and soft tissues including ligaments as well as in the fibrocartilage covering osteophytes. The results support a phasic development of OA with early matrix remodeling and transcriptional activity followed by a more quiescent period that is not maintained. This implies that the response to an OA intervention will depend on the timing of the intervention. The quiescent period at 8 weeks may be due to the maturation of the osteophytes which are thought to temporarily stabilize the joint.
authors: Department of Internal Medicine, Section of Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA. rloeser@wakehealth.edu
authors: Richard F
authors: RF
authors: Loeser
authors: Amy L
authors: AL
authors: Olex
authors: Margaret A
authors: MA
authors: McNulty
authors: Cathy S
authors: CS
authors: Carlson
authors: Michael
authors: M
authors: Callahan
authors: Cristin
authors: C
authors: Ferguson
authors: Jacquelyn S
authors: JS
authors: Fetrow
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental; D002358:Cartilage, Articular / Q000473:pathology; D016000:Cluster Analysis; D024061:Collagen Type III / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D000071235:Fibromodulin; D015870:Gene Expression; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D007596:Joints / Q000473:pathology; D008297:Male; D051379:Mice; D058977:Molecular Sequence Annotation; D010003:Osteoarthritis / Q000235:genetics* / Q000473:pathology*; D011509:Proteoglycans / Q000235:genetics / Q000378:metabolism
chemical_list: D024061:Collagen Type III; D016326:Extracellular Matrix Proteins; C000604332:Fmod protein, mouse; D006023:Glycoproteins; C490748:Prelp protein, mouse; D011509:Proteoglycans; D000071235:Fibromodulin
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