间充质干细胞外泌体在骨关节炎的应用与前景

doi:10.3877/cma.j.issn.1674-134X.2026.01.008

骨关节炎（OA）作为一种全关节退行性疾病，传统治疗难以逆转软骨退变，而间充质干细胞来源的外泌体（MSC-Exo）凭借其稳定性、低免疫原性及靶向递送能力，展现出巨大潜力。MSC-Exo通过调控软骨细胞代谢平衡、增强软骨基质生成及巨噬细胞极化，抑制炎症级联反应，从而延缓OA进展。近年来，工程化外泌体的研究取得突破，如通过靶向肽修饰或纳米技术优化外泌体的载药能力和治疗效果，为OA治疗提供了新思路。然而，MSC-Exo的临床转化仍面临诸多挑战，包括制备方法标准化、作用机制的深入解析以及临床研究数据的不足。本文聚焦于MSC-Exo在OA治疗中的应用前景与挑战作一综述。

关键词: 间质干细胞, 外泌体, 骨关节炎, 软骨, 再生

Osteoarthritis (OA), as a whole-joint degenerative disease, is difficult to reverse cartilage degeneration through traditional treatments. Mesenchymal stem cell-derived exosomes (MSC-Exo) have shown great potential due to their stability, low immunogenicity, and targeted delivery ability. MSC-Exo can delay the progression of OA by regulating the metabolic balance of chondrocytes, enhancing cartilage matrix production, and macrophage polarization, and inhibiting the inflammatory cascade reaction. In recent years, research on engineered exosomes has made breakthroughs, such as optimizing the drug-loading capacity and therapeutic effect of exosomes through targeted peptide modification or nanotechnology, providing new ideas for OA treatment. However, the clinical translation of MSC-Exo still faces many challenges, including the standardization of preparation methods, in-depth analysis of mechanisms of action, and the lack of clinical research data. This article reviewed the application prospects and challenges of MSC-Exo in OA treatment.

Key words: Mesenchymal stem cells, Exosomes, Osteoarthritis, Cartilage, Regeneration

[1]	Hunter DJ, Bierma-Zeinstra S. Osteoarthritis[J]. Lancet, 2019, 393（10182）: 1745-1759.
[2]	Boer CG, Hatzikotoulas K, Southam L, et al. Deciphering osteoarthritis genetics across 826, 690 individuals from 9 populations[J]. Cell, 2021, 184（24）: 6003-6005.
[3]	Grandi FC, Bhutani N. Epigenetic therapies for osteoarthritis[J]. Trends Pharmacol Sci, 2020, 41（8）: 557-569.
[4]	Gou Y, Huang Y, Luo W, et al. Adipose-derived mesenchymal stem cells （MSCs） are a superior cell source for bone tissue engineering[J]. Bioact Mater, 2023, 34: 51-63.
[5]	Cui SH, Yan Y, Lu A, et al. Nanomedicines promote cartilage regeneration in osteoarthritis by synergistically enhancing chondrogenesis of mesenchymal stem cells and regulating inflammatory environment[J]. ACS Nano, 2024, 18（11）: 8125-8142.
[6]	Arya SB, Collie SP, Parent CA. The ins-and-outs of exosome biogenesis, secretion, and internalization[J]. Trends Cell Biol, 2024, 34（2）: 90-108.
[7]	Lai JJ, Chau ZL, Chen SY, et al. Exosome processing and characterization approaches for research and technology development[J/OL]. Adv Sci （Weinh）, 2022, 9（15）: e2103222. DOI:10.1002/advs.202103222.
[8]	Chen M, Liu Y, Cao Y, et al. Remodeling the proinflammatorymicroenvironment in osteoarthritis through interleukin-1 beta tailored exosome cargo for inflammatory regulation and cartilage regeneration[J]. ACS Nano, 2025, 19（4）: 4924-4941.
[9]	Wu Y, Li J, Zeng Y, et al. Exosomes rewire the cartilage microenvironment in osteoarthritis: from intercellular communication to therapeutic strategies[J/OL]. Int J Oral Sci, 2022, 14（1）: 40. DOI:10.1038/s41368-022-00187-z.
[10]	Xu X, Liang Y, Li X, et al. Exosome-mediated delivery of kartogenin for chondrogenesis of synovial fluid-derived mesenchymal stem cells and cartilage regeneration[J/OL]. Biomaterials, 2021, 269: 120539.DOI:10.1016/j.biomaterials.2020.120539.
[11]	Wan J, He Z, Peng R, et al. Injectable photocrosslinking spherical hydrogel-encapsulated targeting peptide-modified engineered exosomes for osteoarthritis therapy[J/OL]. J Nanobiotechnology, 2023, 21（1）: 284. DOI:10.1186/s12951-023-02050-7.
[12]	Wu J, Wu J, Xiang W, et al. Engineering exosomes derived from TNF-α preconditioned IPFP-MSCs enhance both yield and therapeutic efficacy for osteoarthritis[J/OL]. J Nanobiotechnology, 2024, 22（1）: 555. DOI:10.1186/s12951-024-02795-9.
[13]	Pang L, Jin H, Lu Z, et al. Treatment with mesenchymal stem cell-derived nanovesicle-containing gelatin methacryloylhydrogelsalleviates osteoarthritis by modulating chondrogenesis and macrophage polarization[J/OL]. Adv Healthc Mater, 2023, 12（17）: e2300315. DOI:10.1002/adhm.202300315.
[14]	Song X, Xiao J, Ai X, et al. An injectable thermosensitive hydrogel delivering M2 macrophage-derived exosomes alleviates osteoarthritis by promoting synovial lymphangiogenesis[J]. Acta Biomater, 2024, 189: 130-142.
[15]	Kilchert C, Wittmann S, Vasiljeva L. The regulation and functions of the nuclear RNA exosome complex[J]. Nat Rev Mol Cell Biol, 2016, 17（4）: 227-239.
[16]	Zhang Y, Hao Z, Wang P, et al. Exosomes from human umbilical cord mesenchymal stem cells enhance fracture healing through HIF-1α-mediated promotion of angiogenesis in a rat model of stabilized fracture[J/OL]. Cell Prolif, 2019, 52（2）: e12570. DOI:10.1111/cpr.12570.
[17]	Hu Q, Su H, Li J, et al. Clinical applications of exosome membrane proteins[J]. Precis Clin Med, 2020, 3（1）: 54-66.
[18]	Nabhan JF, Hu R, Oh RS, et al. Formation and release of arrestin domain-containing protein 1-mediated microvesicles （ARMMs） at plasma membrane by recruitment of TSG101 protein[J]. Proc Natl Acad Sci USA, 2012, 109（11）: 4146-4151.
[19]	Rhyan Puno M, Lima CD. Structural basis for RNA surveillance by the human nuclear exosome targeting （NEXT） complex[J]. Cell, 2022, 185（12）: 2132-2147.e26.
[20]	Théry C, Zitvogel L, Amigorena S. Exosomes: composition, biogenesis and function[J]. Nat Rev Immunol, 2002, 2（8）: 569-579.
[21]	Maas SLN, Breakefield XO, Weaver AM. Extracellular vesicles: unique intercellular delivery vehicles[J]. Trends Cell Biol, 2017, 27（3）: 172-188.
[22]	Puno MR, Weick EM, Das M, etal. SnapShot: the RNA exosome[J]. Cell, 2019, 179（1）: 282-282.e1.
[23]	Su Y, Ai S, Shen Y, et al. Regulatory effects of three-dimensional cultured lipopolysaccharide-pretreated periodontal ligament stem cell-derived secretome on macrophages[J/OL]. Int J Mol Sci, 2023, 24（8）: 6981. DOI:10.3390/ijms24086981.
[24]	Gurunathan S, Kang MH, Jeyaraj M, et al. Review of the isolation, characterization, biological function, and multifarious therapeutic approaches of exosomes[J/OL]. Cells, 2019, 8（4）: 307. DOI:10.3390/cells8040307.
[25]	Jeppesen DK, Hvam ML, Primdahl-Bengtson B, et al. Comparative analysis of discrete exosome fractions obtained by differential centrifugation[J/OL]. J Extracell Vesicles, 2014, 3: 25011.DOI:10.3402/jev.v3.25011.
[26]	Liu J, Chen B, Bao J, et al. Macrophage polarization in periodontal ligament stem cells enhanced periodontal regeneration[J/OL]. Stem Cell Res Ther, 2019, 10（1）: 320. DOI:10.1186/s13287-019-1409-4.
[27]	Liu B, Xian Y, Chen X, et al. Inflammatory fibroblast-like synoviocyte-derived exosomes aggravate osteoarthritis via enhancing macrophage glycolysis[J/OL]. Adv Sci, 2024, 11（14）: e2307338. DOI:10.1002/advs.202307338.
[28]	Li X, Si Y, Liang J, et al. Enhancing bone regeneration and immunomodulation via gelatin methacryloyl hydrogel-encapsulated exosomes from osteogenic pre-differentiated mesenchymal stem cells[J]. J Colloid Interface Sci, 2024, 672: 179-199.
[29]	Gao S, Mao F, Zhang B, et al. Mouse bone marrow-derived mesenchymal stem cells induce macrophage M2 polarization through the nuclear factor-κB and signal transducer and activator of transcription 3 pathways[J]. Exp Biol Med, 2014, 239（3）: 366-375.
[30]	Colombini A, Ragni E, Mortati L, et al. Adipose-derived mesenchymal stromal cells treated with interleukin 1 beta produced chondro-protective vesicles able to fast penetrate in cartilage[J/OL]. Cells, 2021, 10（5）: 1180. DOI:10.3390/cells10051180.
[31]	Song Y, Dou H, Li X, et al. Exosomal miR-146a contributes to the enhanced therapeutic efficacy of interleukin-1β-primed mesenchymal stem cells against sepsis[J]. Stem Cells, 2017, 35（5）: 1208-1221.
[32]	Liu H, Liang Z, Wang F, et al. Exosomes from mesenchymal stromal cells reduce murine colonic inflammation via a macrophage-dependent mechanism[J/OL]. JCI Insight, 2019, 4（24）: e131273. DOI:10.1172/jci.insight.131273.
[33]	Zhang P, Wu P, Khan UZ, et al. Exosomes derived from LPS-preconditioned bone marrow-derived MSC modulate macrophage plasticity to promote allograft survival via the NF-κB/NLRP3 signaling pathway[J/OL]. J Nanobiotechnology, 2023, 21（1）: 332. DOI:10.1186/s12951-023-02087-8.
[34]	Wang Y, Yu D, Liu Z, et al. Exosomes from embryonic mesenchymal stem cells alleviate osteoarthritis through balancing synthesis and degradation of cartilage extracellular matrix[J/OL]. Stem Cell Res Ther, 2017, 8（1）: 189. DOI:10.1186/s13287-017-0632-0.
[35]	Zhang S, Chuah SJ, Lai RC, et al. MSC exosomes mediate cartilage repair by enhancing proliferation, attenuating apoptosis and modulating immune reactivity[J]. Biomaterials, 2018, 156: 16-27.
[36]	Yan Z, Yin H, Wu J, et al. Engineering exosomes by three-dimensional porous scaffold culture of human umbilical cord mesenchymal stem cells promote osteochondral repair[J/OL]. Mater Today Bio, 2023, 19: 100549.DOI:10.1016/j.mtbio.2023.100549.
[37]	Cosenza S, Ruiz M, Toupet K, et al. Mesenchymal stem cells derived exosomes and microparticles protect cartilage and bone from degradation in osteoarthritis[J/OL]. Sci Rep, 2017, 7（1）: 16214. DOI:10.1038/s41598-017-15376-8.
[38]	Bousnaki M, Bakopoulou A, Kritis A, et al. The efficacy of stem cells secretomeapplication in osteoarthritis: asystematicreview of in vivo studies[J]. Stem Cell Rev Rep, 2020, 16（6）: 1222-1241.
[39]	Zhou H, Shen X, Yan C, et al. Extracellular vesicles derived from human umbilical cord mesenchymal stem cells alleviate osteoarthritis of the knee in mice model by interacting with METTL3 to reduce m6A of NLRP3 in macrophage[J/OL]. Stem Cell Res Ther, 2022, 13（1）: 322. DOI:10.1186/s13287-022-03005-9.
[40]	Wang C, Al-Ani MK, Sha Y, et al. Psoralen protects chondrocytes, exhibits anti-inflammatory effects on synoviocytes, and attenuates monosodium iodoacetate-induced osteoarthritis[J]. Int J Biol Sci, 2019, 15（1）: 229-238.
[41]	Tong W, Zeng Y, Chow DHK, et al. Wnt16 attenuates osteoarthritis progression through a PCP/JNK-mTORC1-PTHrP cascade[J]. Ann Rheum Dis, 2019, 78（4）: 551-561.
[42]	Meeson RL, Todhunter RJ, Blunn G, et al. Spontaneous dog osteoarthritis - a one medicine vision[J]. Nat Rev Rheumatol, 2019, 15（5）: 273-287.
[43]	Wiegant K, Intema F, van Roermund PM, et al. Evidence of cartilage repair by joint distraction in a canine model of osteoarthritis[J]. Arthritis Rheumatol, 2015, 67（2）: 465-474.
[44]	Cai D, Zhang J, Yang J, et al. Overexpression of FTO alleviates osteoarthritis by regulating the processing of miR-515-5p and the TLR4/MyD88/NF-κB axis[J/OL]. Int Immunopharmacol, 2023, 114: 109524. DOI:10.1016/j.intimp.2022.109524.
[45]	Li F, Xu Z, Xie Z, et al. Adipose mesenchymal stem cells-derived exosomes alleviate osteoarthritis by transporting microRNA-376c-3p and targeting the WNT-beta-catenin signaling axis[J]. Apoptosis, 2023, 28（3-4）: 362-378.
[46]	XieRH, Gong SG, Song J, et al. Effect of mesenchymal stromal cells transplantation on the outcomes of patients with knee osteoarthritis: a systematic review and meta-analysis[J]. J Orthop Res, 2024, 42（4）: 753-768.
[47]	ZununiVahed S, Hejazian SM, Bakari WN, et al. Milking mesenchymal stem cells: Updated protocols for cell lysate, secretome, and exosome extraction, and comparative analysis of their therapeutic potential[J]. Methods, 2025, 238: 40-60.
[48]	Zhou Q, Cai Y, Jiang Y, et al. Exosomes in osteoarthritis and cartilage injury: advanced development and potential therapeutic strategies[J]. Int J Biol Sci, 2020, 16（11）: 1811-1820.
[49]	Zhao Q, Mo Z, Zeng L, etal. Construction and evaluation of hepatic targeted drug delivery system with hydroxycamptothecin in stem cell-derived exosomes[J/OL]. Molecules, 2024, 29（21）: 5174. DOI:10.3390/molecules29215174.
[50]	Forró T, Bajkó Z, Bălașa A, etal. Dysfunction of the neurovascular unit in ischemic stroke: highlights on microRNAs and exosomes as potential biomarkers and therapy[J/OL]. Int J Mol Sci, 2021, 22（11）: 5621. DOI:10.3390/ijms22115621.
[51]	Sun H, Hu S, Zhang Z, et al. Expression of exosomal microRNAs during chondrogenic differentiation of human bone mesenchymal stem cells[J]. J Cell Biochem, 2019, 120（1）: 171-181.
[52]	Batagov AO, Kuznetsov VA, Kurochkin IV. Identification of nucleotide patterns enriched in secreted RNAs as putative Cis-acting elements targeting them to exosome nano-vesicles[J/OL]. BMC Genomics, 2011, 12（Suppl 3）: S18. DOI:10.1186/1471-2164-12-S3-S18.
[53]	Lin Y, Wu J, Gu W, et al. Exosome-liposome hybrid nanoparticles deliver CRISPR/Cas9 system in MSCs[J/OL]. Adv Sci, 2018, 5（4）: 1700611. DOI:10.1002/advs.201700611.
[54]	Chen P, Zheng L, Wang Y, et al. Desktop-stereolithography 3D printing of a radially oriented extracellular matrix/mesenchymal stem cell exosome bioink for osteochondral defect regeneration[J]. Theranostics, 2019, 9（9）: 2439-2459.
[55]	Wu X, Tao W, Lan Z, et al. pH-responsive engineered exosomes enhance endogenous hyaluronanproduction by reprogramming chondrocytes for cartilage repair[J/OL]. Adv Healthc Mater, 2025, 14（10）: e2405126. DOI:10.1002/adhm.202405126.
[56]	Ni Z, Zhou S, Li S, et al. Exosomes: roles and therapeutic potential in osteoarthritis[J/OL]. Bone Res, 2020, 8: 25. DOI:10.1038/s41413-020-0100-9.
[57]	Liang Y, Xu X, Xu L, et al. Chondrocyte-specific genomic editing enabled by hybrid exosomes for osteoarthritis treatment[J]. Theranostics, 2022, 12（11）: 4866-4878.
[58]	Bei HP, Hung PM, Yeung HL, et al. Bone-a-petite: engineering exosomes towards bone, osteochondral, and cartilage repair[J/OL]. Small, 2021, 17（50）: e2101741. DOI:10.1002/smll.202101741.
[59]	Zhang H, Yan W, Wang J, et al. Surface functionalization of exosomes for chondrocyte-targeted siRNA delivery and cartilage regeneration[J]. J Control Release, 2024, 369: 493-505.
[60]	Wu J, Kuang L, Chen C, et al. miR-100-5p-abundant exosomes derived from infrapatellar fat pad MSCs protect articular cartilage and ameliorate gait abnormalities via inhibition of mTOR in osteoarthritis[J]. Biomaterials, 2019, 206: 87-100.
[61]	Jan A, Sofi S, Jan N, et al. An update on cancer stem cell survival pathways involved in chemoresistance in triple-negative breast cancer[J]. Future Oncol, 2025, 21（6）: 715-735.
[62]	Yang L, Li W, Zhao Y, et al. Magnetic polysaccharide mesenchymal stem cells exosomes delivery microcarriers for synergistic therapy of osteoarthritis[J/OL]. ACS Nano, 2024.DOI:10.1021/acsnano.4c01406.
[63]	Jafari D, Malih S, Eini M, et al. Improvement, scaling-up, and downstream analysis of exosome production[J]. Crit Rev Biotechnol, 2020, 40（8）: 1098-1112.
[64]	Zhang Y, Liu Y, Liu H, etal. Exosomes: biogenesis, biologic function and clinical potential[J/OL]. Cell Biosci, 2019, 9: 19. DOI:10.1186/s13578-019-0282-2.
[65]	Lener T, Gimona M, Aigner L, et al. Applying extracellular vesicles based therapeutics in clinical trials - an ISEV position paper[J/OL]. J Extracell Vesicles, 2015, 4: 30087. DOI:10.3402/jev.v4.30087.
[66]	Kim JY, Rhim WK, YooYI, et al. Defined MSC exosome with high yield and purity to improve regenerative activity[J/OL]. J Tissue Eng, 2021, 12: 20417314211008626. DOI:10.1177/20417314211008626.
[67]	Zhang C, Pathrikar TV, Baby HM, et al. Charge-reversed exosomes for targeted gene delivery to cartilage for osteoarthritis treatment[J/OL]. Small Methods, 2024, 8（9）: e2301443. DOI:10.1002/smtd.202301443.
[68]	Théry C, Witwer KW, Aikawa E, et al. Minimal information for studies of extracellular vesicles 2018 （MISEV2018）: a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines[J/OL]. J Extracell Vesicles, 2018, 7（1）: 1535750. DOI:10.1080/20013078.2018.1535750.
[69]	Wang C, Qiu J, Liu M, et al. Microfluidic biochips for single-cell isolation and single-cell analysis of multiomics and exosomes[J/OL]. Adv Sci, 2024, 11（28）: e2401263. DOI:10.1002/advs.202401263.
[70]	Copp G, Robb KP, Viswanathan S. Culture-expanded mesenchymal stromal cell therapy: does it work in knee osteoarthritis? A pathway to clinical success[J]. Cell Mol Immunol, 2023, 20（6）: 626-650.
[71]	Zhu F, Wang T, Wang G, et al. The exosome-mediated bone regeneration: an advanced horizon toward the isolation, engineering, carrying modalities, and mechanisms[J/OL]. Adv Healthc Mater, 2024, 13（19）: e2400293. DOI:10.1002/adhm.202400293.
[72]	Nouri Z, Barfar A, Perseh S, et al. Exosomes as therapeutic and drug delivery vehicle for neurodegenerative diseases[J/OL]. J Nanobiotechnology, 2024, 22（1）: 463. DOI:10.1186/s12951-024-02681-4.
[73]	Selvadoss A, Baby HM, Zhang H, et al. Harnessing exosomes for advanced osteoarthritis therapy[J]. Nanoscale, 2024, 16（41）: 19174-19191.

[1]	刘锦婷, 梁高强, 李文涛. 乳房切除术后感觉功能重建的研究进展[J/OL]. 中华乳腺病杂志(电子版), 2025, 19(06): 358-361.
[2]	中华医学会骨科学分会关节外科学组, 王坤正, 史占军, 曲铁兵. 中国膝骨关节炎关节腔注射治疗专家共识（2026版）[J/OL]. 中华关节外科杂志(电子版), 2026, 20(01): 1-14.
[3]	李亚鹏, 岳辰, 李峰, 张志杰, 成彦, 郭珈宜. 膝骨关节炎膝周肌肉硬度与功能的相关性评估[J/OL]. 中华关节外科杂志(电子版), 2026, 20(01): 32-40.
[4]	刘肖雅, 郭珈宜, 成彦, 李峰, 杨艳霞, 高起, 杨玉霞, 岳辰. 虚拟现实运动在膝骨关节炎患者中应用效果的Meta分析[J/OL]. 中华关节外科杂志(电子版), 2026, 20(01): 50-59.
[5]	潘子杭, 杨丽华, 孙轶群, 丁美军, 薛珂. 表皮干细胞来源外泌体在创面修复中应用的研究进展[J/OL]. 中华损伤与修复杂志(电子版), 2026, 21(01): 58-62.
[6]	杨浩, 王春岭, 席少华, 尹素然. 富血小板血浆联合关节镜手术治疗膝骨关节炎的疗效分析[J/OL]. 中华损伤与修复杂志(电子版), 2025, 20(06): 499-504.
[7]	陈静, 曲东, 刘霜. 急性呼吸窘迫综合征细胞治疗机制及临床应用研究进展[J/OL]. 中华实验和临床感染病杂志(电子版), 2025, 19(06): 327-334.
[8]	曾慧, 刘朝朝, 牛雷, 邓雅洁, 徐礼霞, 沙莎. 早期肺腺癌血清外泌体miRNA特征谱及诊断标志物筛选研究[J/OL]. 中华肺部疾病杂志(电子版), 2025, 18(06): 891-896.
[9]	徐倩, 魏凤香. 干细胞：开启精神疾病治疗的新曙光[J/OL]. 中华细胞与干细胞杂志(电子版), 2026, 16(01): 52-55.
[10]	吴刚, 严燃星, 严鑫, 阎婧, 何跃明, 朱倩. 基于血清和组织外泌体多组学分析筛选胰腺癌诊断和预后标志物[J/OL]. 中华肝脏外科手术学电子杂志, 2025, 14(06): 962-972.
[11]	郑富文, 马阳, 唐金烁, 彭亚臣, 左建林. 导航TKA术后引流放置与否对患者预后影响：一项队列研究[J/OL]. 中华老年骨科与康复电子杂志, 2025, 11(06): 329-336.
[12]	侯芳红, 贺修宝. 超声介导的雷公藤甲素外泌体靶向给药系统抗结直肠癌的应用评估[J/OL]. 中华消化病与影像杂志(电子版), 2026, 16(01): 13-20.
[13]	王小娟, 王一菲, 冯莉, 周发明, 杨玉华, 叶艳华, 许云涛. 血清再生胰岛衍生蛋白3α与降钙素原对胆总管结石患者内镜逆行胰胆管造影术后胰腺炎的预测价值[J/OL]. 中华消化病与影像杂志(电子版), 2026, 16(01): 67-72.
[14]	王兆彤, 王美琴, 陈磊, 王莹莹, 吴军, 苑小历. 重复性经颅磁刺激与外泌体：抑郁症治疗研究的新视角[J/OL]. 中华临床医师杂志(电子版), 2025, 19(11): 866-870.
[15]	希龙夫, 李江涛. CXCL12及其受体CXCR4/CXCR7在肝脏相关疾病中的研究进展[J/OL]. 中华临床医师杂志(电子版), 2025, 19(09): 714-719.

阅读次数

全文

摘要

选择文件类型/文献管理软件名称

选择包含的内容

Application and prospects of mesenchymal stem cell-derived exosomes in osteoarthritis

模态框（Modal）标题

选择文件类型/文献管理软件名称

选择包含的内容

Application and prospects of mesenchymal stem cell-derived exosomes in osteoarthritis