六、小结
理想的OA动物模型应该具备较好的可行性和可重复性，并能最大限度地复制人类OA的病变特征。外科手术诱导关节不稳是目前最为常用的OA造模方法。内侧半月板失稳 (DMM)模型由于保留了内侧半月板的完整性，对实验动物造成的损伤较轻，模型较易获得。重要的是，它能很好地展现OA缓慢的病变过程，如今已广泛应用于OA相关基础研究中。半月板韧带损伤术 (MLI)模型则通过不同术式的组合复制了不同严重程度的OA病变特征，为OA不同发展阶段的组织病理学及分子机制的探索奠定了基础。而基因工程技术的飞速发展则推动了OA发病机制的研究深入到基因和分子水平，同时为治疗药物的筛选提供了良好的平台。此外，组织病理学、同步辐射X线相位成像、Micro-CT、免疫组化等技术在OA动物模型评估中的应用进一步深化了OA的基础研究。随着科技的不断进步，相信不久的将来，OA相关评估研究方法将会越来越丰富。
（张 磊 沈 杰 陈 棣）
参考文献
［1］Felson DT.Clinical practice.Osteoarthritis of the knee.N Engl J Med，2006，354：841-848.
［2］Goldring MB，Goldring SR.Osteoarthritis.JCell Physiol，2007，213：626-634.
［3］Doherty M.Risk factors for progression of knee osteoarthritis.Lancet，2001，358：775-6.
［4］Haywood L，McWilliams DF，Pearson CI，et al.Inflammation and angiogenesis in osteoarthritis.Arthritis Rheum，2003，48：2173-7.
［5］Haq I，Murphy E，Dacre J.Osteoarthritis.Postgrad Med J，2003，79：377-83.
［6］Brandt KD.Animalmodels：insights into osteoarthritis(OA)provided by the cruciate-deficient dog.Br JRheumatol，1991，30(Suppl 1)：5-9.
［7］Brandt KD.Animal models of osteoarthritis.Biorheology，2002，39：221-35.
［8］Bendele AM.Animalmodels of osteoarthritis.JMusculoskelet Neuron Interact，2001，1：363-76.
［9］Hayami T，PickarskiM，Wesolowski GA，et al.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.Arthritis Rheum，2004，50：1193-206.
［10］Pacifici M，Koyama E，Iwamoto M.Mechanisms of synovial joint and articular cartilage formation：recent advances，butmany lingeringmysteries.Birth Defects Res C Embryo Today，2005，75：237-248.
［11］Goldring MB，Goldring SR.Articular cartilage and subchondral bone in the pathogenesis of osteoarthritis.Ann N Y Acad Sci，2010，1192：230-237.
［12］Mort JS，Billington CJ.Articular cartilage and changes in arthritis：matrix degradation.Arthritis Res，2001，3：337-341.
［13］Jacobsen K.Osteoarthrosis following insufficiency of the cruciate ligaments in man.A clinical study.Acta Orthop Scand，1977，48：520-6.
［14］Roos H，Adalberth T，Dahlberg L，et al.Osteoarthritis of the knee after injury to the anterior cruciate ligament ormeniscus：the influence of time and age.Osteoarthritis Cartilage，1995，3：261-7.
［15］Brandt KD，Braunstein EM，Visco DM，et al.Anterior(cranial)cruciate ligament transection in the dog：a bona fidemodel of osteoarthritis，notmerely of cartilage injury and repair.JRheumatol，1991，18：436-46.
［16］Oegema TR，Visco D.Animal Models of Osteoarthritis.In：An YH，Friedman RJ，Eds.BocaRaton：CRC Press，1999：349-67.
［17］Griffiths RJ，Schrier DJ.In：Brandt KD，Doherty M，Lohmander LS，Eds. Advantages and Limitations of Animals Models in the Discovery and Evaluation of Novel Disease-modifying Osteoarthritis Drugs(DMOADs).Oxford：Oxford University Press，2003：411-6.
［18］Glasson SS，Blanchet TJ，Morris EA.The surgicaldestabilization of themedial meniscus(DMM)model of osteoarthritis in the 129/SvEvmouse.Osteoarthritis Cartilage，2007，15(9)：1061-9.
［19］Ma H-L，Blanchet T，Morris EA，etal.Disease progression in surgicallyinduced murine osteoarthritis is strain and sex dependent.Trans Orthop Res Soc，2005，30：1422.
［20］Glasson SS，Askew R，Sheppard B，et al.Deletion of active ADAMTS5 prevents cartilage degradation in amurinemodel of osteoarthritis.Nature，2005，434：644-8.
［21］Glasson SS，Blanchet TJ，Morris EA.Less severe OA is observed in the IL-1 beta KO and more severe OA is observed in the MMP-9 and MK2 KOmice in a surgicalmodel of OA.Trans Orthop Res Soc，2005，51：251.
［22］Kamekura S，Hoshi K，Shimoaka T.Osteoarthritis development in novel experimental mouse models induced by knee joint instability.Osteoarthritis Cartilage，2005，13(7)：632-41.
［23］Poole AR.An introduction to the pathophysiology of osteoarthritis.Front Biosci，1999，4：D662-70.
［24］Santori N，Villar RN.Arthroscopic findings in the initial stages of hip osteoarthritis.Orthopedics，1999，22：405-9.
［25］Bendele AM.Animalmodels of osteoarthritis.JMusculoskelet Neuron Interact，2001，1：363-76.
［26］Walton M.Patella displacement and osteoarthrosis of the knee joint in mice. JPathol，1979，127：165-72.
［27］WilhelmiG，Faust R.Suitability of the C57 black mouse as an experimental animal for the study of skeletal changes due to ageing，with special reference to osteo-arthrosis and its response to tribenoside.Pharmacology，1976，14：289-96.
［28］Saamanen AK，Salminen HJ，Dean PB，et al.Osteoarthritis-like lesions in transgenicmice harboring a small deletionmutation in type IIcollagen gene.Osteoarthritis Cartilage，2000，8：248-57.
［29］Blaney Davidson EN，van der Kraan PM，van den BergWB.TGF-beta and osteoarthritis.Osteoarthritis Cartilage，2007，15：597-604.(https://www.daowen.com)
［30］Serra R，Johnson M，Filvaroff EH，et al.Expression of a truncated，kinase-defective TGF-beta type II receptor inmouse skeletal tissue promotes terminal chondrocyte differentiation and osteoarthritis.J Cell Biol，1997，139：541-552.
［31］Yang X，Chen L，Xu X，et al.TGF-beta/Smad3 signals repress chondrocyte hypertrophic differentiation and are required for maintaining articular cartilage.JCell Biol，2001，153：35-46.
［32］Spector TD，MacGregor AJ.Risk factors for osteoarthritis：genetics.Osteoarthritis Cartilage，2004，12 Suppl A：S39-44.
［33］Shen J，Li J，Wang B，et al.Deletion of the transforming growth factor beta receptor type IIgene in articular chondrocytes leads to a progressive osteoarthritis-like phenotype in mice.Arthritis Rheum，2013，65：3107-3119.
［34］Valdes AM，Spector TD，Tamm A，et al.Genetic variation in the Smad3 gene is associated with hip and knee osteoarthritis.Arthritis Rheum，2010，62：2347-2352.
［35］Yang Y.Wnts and wing：Wnt signaling in vertebrate limb development and musculoskeletalmorphogenesis.Birth Defects Res C Embryo Today，2003，69：305-317.
［36］Zhu M，Tang D，Wu Q，etal.Activation of beta-catenin signaling in articular chondrocytes leads to osteoarthritis-like phenotype in adult beta-catenin conditional activation mice.JBone Miner Res，2009，24：12-21.
［37］Clevers H.Wnt/beta-catenin signaling in development and disease.Cell，2006，127：469-480.
［38］Loughlin J，Dowling B，Chapman K，et al.Functional variantswithin the secreted frizzled-related protein 3 gene are associated with hip osteoarthritis in females.Proc Natl Acad Sci U SA，2004，101：9757-9762.
［39］Spector TD，MacGregor AJ.Risk factors for osteoarthritis：genetics.Osteoarthritis Cartilage，2004，12 Suppl A：S39-44.
［40］Slagboom PE，Heijmans BT，Beekman M，et al.Genetics of human aging.The search for genes contributing to human longevity and diseases of the old.Ann N Y Acad Sci，2000，908：50-63.
［41］Loughlin J，Mustafa Z，Smith A，et al.Linkage analysis of chromosome 2q in osteoarthritis.Rheumatology(Oxford)，2000，39：377-381.
［42］Enomoto-Iwamoto M，Kitagaki J，Koyama E，et al.The Wnt antagonist Frzb-1 regulates chondrocyte maturation and long bone development during limb skeletogenesis.Dev Biol，2002，251：142-156.
［43］Tamamura Y，Otani T，Kanatani N，et al.Developmental regulation ofWnt/ beta-catenin signals is required for growth plate assembly，cartilage integrity，and endochondral ossification.JBiol Chem，2005，280：19185-19195.
［44］Lories RJ，Peeters J，Bakker A，et al.Articular cartilage and biomechanical properties of the long bones in Frzb-knockout mice.Arthritis Rheum，2007，56：4095-4103.
［45］Wu Q，Kim KO，Sampson ER，et al.Induction of an osteoarthritis-like phenotype and degradation of phosphorylated Smad3 by Smurf2 in transgenic mice.Arthritis Rheum，2008，58：3132-3144.
［46］Zhu M，Tang D，Wu Q，etal.Activation of beta-catenin signaling in articular chondrocytes leads to osteoarthritis-like phenotype in adult beta-catenin conditional activation mice.JBone Miner Res，2009，24：12-21.
［47］Lin AC，Seeto BL，Bartoszko JM，et al.Modulating hedgehog signaling can attenuate the severity of osteoarthritis.Nat Med，2009，15：1421-1425.
［48］Saito T，Fukai A，Mabuchi A，et al.Transcriptional regulation of endochondral ossification by HIF-2alpha during skeletal growth and osteoarthritis development.Nat Med，2010，16：678-686.
［49］Yang S，Kim J，Ryu JH，et al.Hypoxia-inducible factor-2alpha is a catabolic regulator of osteoarthritic cartilage destruction.Nat Med，2010，16：687-693.
［50］Saito T，Fukai A，Mabuchi A，et al.Transcriptional regulation of endochondral ossification by HIF-2alpha during skeletal growth and osteoarthritis development.Nat Med，2010，16：678-686.
［51］Yang S，Kim J，Ryu JH，et al.Hypoxia-inducible factor-2alpha is a catabolic regulator of osteoarthritic cartilage destruction.Nat Med，2010，16：687-693.
［52］Mankin HJ.Biochemical and metabolic aspects of osteoarthritis.Orthop Clin North Am，1971，2：19-31.
［53］Simon WH.Scale effects in animal joints.I.Articular cartilage thickness and compressive stress.Arthritis Rheum，1970，13：244-56.
［54］Glasson SS，Chambers MG，Van Den Berg WB.The OARSI histopathology initative-recommendations for histological assessments of osteoarthritis in the mouse.Osteoarthritis Cartilage，2010，18 Suppl 3：S17-23.
［55］Chambers MG，Bayliss MT，Mason RM.Chondrocyte cytokine and growth factor expression in murine osteoarthritis.Osteoarthritis Cartilage，1997，5：301-8.
［56］Margaritondo G，Hwu Y，Je JH.Synchrotron light in medical and materials science radiology.Rivistadel Nuovo Cimento，2004，27：1-40.
［57］Yoon JS，Won SJ，Kim SJ，etal.Phase-Contrast Radiography Enables Detection of Early Changes in Articular Cartilage in a Mouse Model of Osteoarthritis.Am JPhys Med Rehabil，2015，94(8)：644-8.
［58］Mollenhauer JA，Aurich ME，Zhong Z，et al.Diffraction-enhanced X-ray imaging of articular cartilage.Osteoarthritis Cartilage，2002，10(3)：163-171.
［59］Thomas NP，Li P，Fleming BC，et al.Attenuation of cartilage pathogenesis in post-traumatic osteoarthritis(PTOA)inmice by blocking the stromal derived factor 1 receptor(CXCR4)with the specific inhibitor，AMD3100.J Orthop Res，2015，33(7)：1071-8.