AbstractMechanical overloading and aging are two essential factors for osteoarthritis (OA) development. Mitochondria have been identified as a mechano-transducer situated between extracellular mechanical signals and chondrocyte biology, but their roles and the associated mechanisms in mechanical stress-associated chondrocyte senescence and OA have not been elucidated.

摘要机械过载和衰老是骨关节炎（OA）发展的两个重要因素。线粒体已被确定为位于细胞外机械信号和软骨细胞生物学之间的机械换能器，但它们在机械应力相关的软骨细胞衰老和OA中的作用和相关机制尚未阐明。

Herein, we found that PDZ domain containing 1 (PDZK1), one of the PDZ proteins, which belongs to the Na+/H+ Exchanger (NHE) regulatory factor family, is a key factor in biomechanically induced mitochondrial dysfunction and chondrocyte senescence during OA progression. PDZK1 is reduced by mechanical overload, and is diminished in the articular cartilage of OA patients, aged mice and OA mice.

。PDZK1因机械过载而减少，并且在OA患者，老年小鼠和OA小鼠的关节软骨中减少。

Pdzk1 knockout in chondrocytes exacerbates mechanical overload-induced cartilage degeneration, whereas intraarticular injection of adeno-associated virus-expressing PDZK1 had a therapeutic effect. Moreover, PDZK1 loss impaired chondrocyte mitochondrial function with accumulated damaged mitochondria, decreased mitochondrion DNA (mtDNA) content and increased reactive oxygen species (ROS) production.

软骨细胞中的Pdzk1敲除加剧了机械超负荷诱导的软骨变性，而关节内注射表达Pdzk1的腺相关病毒具有治疗效果。此外，PDZK1丢失会损害软骨细胞线粒体功能，线粒体受损，线粒体DNA（mtDNA）含量降低，活性氧（ROS）产生增加。

PDZK1 supplementation or mitoubiquinone (MitoQ) application alleviated chondrocyte senescence and cartilage degeneration and significantly protected chondrocyte mitochondrial functions. MRNA sequencing in articular cartilage from Pdzk1 knockout mice and controls showed that PDZK1 deficiency in chondrocytes interfered with mitochondrial function through inhibiting Hmgcs2 by increasing its ubiquitination.

PDZK1补充剂或mitoubiquinone（MitoQ）应用可减轻软骨细胞衰老和软骨变性，并显着保护软骨细胞线粒体功能。Pdzk1基因敲除小鼠和对照组关节软骨中的MRNA测序表明，软骨细胞中Pdzk1缺陷通过增加Hmgcs2的泛素化来抑制线粒体功能。

Our results suggested that PDZK1 deficiency plays a crucial role in mediating excessive mechanical load-induced chondrocyte senescence and is associated with mitochondrial dysfunction. PDZK1 overexpression or preservation of mi.

我们的研究结果表明，PDZK1缺陷在介导过度机械负荷诱导的软骨细胞衰老中起着至关重要的作用，并与线粒体功能障碍有关。PDZK1过表达或保存mi。

IntroductionOsteoarthritis (OA) is the most common degenerative joint disorder that represents a leading cause of disability and source of socioeconomic cost in older adults.1,2,3 It is recognized that mechanical overloading and advanced age are the main risk factors involved in OA pathogenesis, but the mechanisms have, to date, not been elucidated.4,5,6In our previous study, we found that excessive mechanical overload promoted chondrocyte senescence and OA development.7 However, the molecular and cellular mechanisms that underlie the transduction of physical signals to biochemical signals resulting in OA progression have not been fully elucidated.8,9,10 Mitochondria, which are membrane-enclosed organelles and produce cellular energy in the form of adenosine11 triphosphate (ATP), are currently a focus of biomedical research because of their role in aging and the development of OA pathologies.12,13 Growing evidence suggests that mitochondrial dysfunction not only leads to cellular senescence, but also accelerates organismal aging via mechanisms associated with mitochondrial reactive oxygen species (ROS) production, mitochondria DNA (mtDNA) mutations and mitochondrial biogenesis.11,14,15,16 Targeted clearance of mitochondrial ROS production can significantly reduce Matrix Metallopeptidase (MMP) secretion by OA chondrocytes and delay OA cartilage degeneration.17,18 Recent studies have identified mitochondria as a critical mechano-transducer situated between extracellular mechanical signals and chondrocyte biology, and their function can be disordered as early as after a few minutes on mechanical overloading, leading to chondrocyte damage.19,20 Therefore, we propose that mitochondria play an important role in chondrocyte senescence resulting from mechanical overload, but th.

引言骨关节炎（OA）是最常见的退行性关节疾病，是老年人残疾的主要原因和社会经济成本的来源。1,2,3人们认识到，机械超负荷和高龄是OA发病机制的主要危险因素，但迄今为止，其机制尚未阐明。4,5,6在我们之前的研究中，我们发现过度的机械超负荷促进了软骨细胞衰老和OA的发展。然而，尚未完全阐明将物理信号转导为生化信号导致OA进展的分子和细胞机制。8,9,10线粒体是膜封闭的细胞器，以腺苷的形式产生细胞能量11三磷酸（ATP）因其在衰老和OA病理发展中的作用而成为生物医学研究的重点。12,13越来越多的证据表明，线粒体功能障碍不仅导致细胞衰老，但也通过与线粒体活性氧（ROS）产生，线粒体DNA（mtDNA）突变和线粒体生物发生相关的机制加速机体衰老[11,14,15,16]。线粒体ROS产生的靶向清除可以显着减少基质金属肽酶（MMP）OA软骨细胞的分泌，延缓OA软骨退变[17,18]。最近的研究已经确定线粒体是位于细胞外机械信号和软骨细胞生物学之间的关键机械换能器，它们的功能早在机械过载几分钟后就可能紊乱，导致软骨细胞损伤[19,20]。因此，我们认为线粒体在机械过载导致的软骨细胞衰老中起重要作用，但th。

Data availability

数据可用性

All data generated or analyzed during this study are included in this submitted article and its additional files. The mRNA sequencing data has been deposited in the NCBlSRA database under accession codes PRINA1080460.

本研究期间生成或分析的所有数据均包含在本文及其附加文件中。mRNA测序数据已以登录号PRINA1080460保存在NCBlSRA数据库中。

ReferencesHunter, D. J. & Bierma-Zeinstra, S. Osteoarthritis. Lancet 393, 1745–1759 (2019).Article

参考文献Hunter，D.J。和Bierma Zeinstra，S。骨关节炎。柳叶刀3931745-1759（2019）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Sharma, L. Osteoarthritis of the Knee. N. Engl. J. Med. 384, 51–59 (2021).Article

Sharma，L。膝关节骨关节炎。N、 英语。J、 医学384,51-59（2021）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Glyn-Jones, S. et al. Osteoarthritis. Lancet 386, 376–387 (2015).Article

Glyn Jones，S。等人。骨关节炎。。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Visser, A. W. et al. The relative contribution of mechanical stress and systemic processes in different types of osteoarthritis: the NEO study. Ann. Rheum. Dis. 74, 1842–1847 (2015).Article

Visser，A.W.等人。机械应力和系统过程在不同类型骨关节炎中的相对贡献：NEO研究。安。瑞姆。Dis。741842-1847（2015）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Coryell, P. R., Diekman, B. O. & Loeser, R. F. Mechanisms and therapeutic implications of cellular senescence in osteoarthritis. Nat. Rev. Rheumatol. 17, 47–57 (2021).Article

Coryell，P.R.，Diekman，B.O。＆Loeser，R.F。细胞衰老在骨关节炎中的机制和治疗意义。风湿病杂志。17，47-57（2021）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Rose, J. et al. DNA damage, discoordinated gene expression and cellular senescence in osteoarthritic chondrocytes. Osteoarthr. Cartil. 20, 1020–1028 (2012).Article

Rose，J.等人。骨关节炎软骨细胞中的DNA损伤，不协调的基因表达和细胞衰老。骨关节。卡蒂尔。201020-1028（2012）。文章

CAS

中科院

Google Scholar

谷歌学者

Zhang, H. et al. Mechanical overloading promotes chondrocyte senescence and osteoarthritis development through downregulating FBXW7. Ann. Rheum. Dis. 81, 676–686 (2022).Article

Zhang，H。等人。机械过载通过下调FBXW7促进软骨细胞衰老和骨关节炎的发展。安。瑞姆。Dis。81676-686（2022）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Griffin, T. M. & Guilak, F. The role of mechanical loading in the onset and progression of osteoarthritis. Exerc. Sport Sci. Rev. 33, 195 (2005).Yuan, X. L. et al. Bone-cartilage interface crosstalk in osteoarthritis: potential pathways and future therapeutic strategies. Osteoarthr. Cartil.

。练习。体育科学。第33195（2005）版。Yuan，X.L.等。骨关节炎中的骨-软骨界面串扰：潜在途径和未来治疗策略。骨关节。卡蒂尔。

22, 1077–1089 (2014).Article .

221077-1089（2014）。文章。

CAS

中科院

Google Scholar

谷歌学者

Zhang, Y. et al. Primary cilium-mediated mechanotransduction in cartilage chondrocytes. Exp. Biol. Med. 248, 1279–1287 (2023).Article

Zhang，Y。等人。软骨细胞中初级纤毛介导的机械转导。实验生物。医学2481279-1287（2023）。文章

CAS

中科院

Google Scholar

谷歌学者

Silva-Pinheiro, P. & Minczuk, M. The potential of mitochondrial genome engineering. Nat. Rev. Genet 23, 199–214 (2022).Article

Silva Pinheiro，P。＆Minczuk，M。线粒体基因组工程的潜力。Nat。Rev。Genet 23199-214（2022）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Chan, D. C. Mitochondrial dynamics and its involvement in disease. Annu Rev. Pathol. 15, 235–259 (2020).Article

Chan，D.C。线粒体动力学及其与疾病的关系。年度修订Pathol。15235-259（2020）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Gorman, G. S. et al. Mitochondrial diseases. Nat. Rev. Dis. Prim. 2, 16080 (2016).Article

Gorman，G.S.等人。线粒体疾病。自然版本Dis。一本正经。216080（2016）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Valdes, A. M. & Goldring, M. B. Mitochondrial DNA haplogroups and ageing mechanisms in osteoarthritis. Ann. Rheum. Dis. 76, 939–941 (2017).Article

Valdes，A.M。＆Goldring，M.B。线粒体DNA单倍群和骨关节炎的衰老机制。安。瑞姆。Dis。76939-941（2017）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Zorov, D. B., Juhaszova, M. & Sollott, S. J. Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol. Rev. 94, 909–950 (2014).Article

Zorov，D.B.，Juhaszova，M。＆Sollott，S.J。线粒体活性氧（ROS）和ROS诱导的ROS释放。生理学。版本94909-950（2014）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Cleveland, K. H. & Schnellmann, R. G. Pharmacological targeting of mitochondria in diabetic kidney disease. Pharm. Rev. 75, 250–262 (2023).Article

Cleveland，K.H。＆Schnellmann，R.G。糖尿病肾病中线粒体的药理学靶向。《药学杂志》第75250-262版（2023年）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Reed, K. N., Wilson, G., Pearsall, A. & Grishko, V. I. The role of mitochondrial reactive oxygen species in cartilage matrix destruction. Mol. Cell Biochem. 397, 195–201 (2014).Article

Reed，K.N.，Wilson，G.，Pearsall，A。＆Grishko，V.I。线粒体活性氧在软骨基质破坏中的作用。分子细胞生物化学。397195-201（2014）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Li, H. et al. Reprogramming macrophage polarization, depleting ROS by astaxanthin and thioketal-containing polymers delivering rapamycin for osteoarthritis treatment. Adv. Sci. (2023).Goetz, J. E. et al. Time-dependent loss of mitochondrial function precedes progressive histologic cartilage degeneration in a rabbit meniscal destabilization model.

Li，H。等人。重编程巨噬细胞极化，通过虾青素和含巯基酮的聚合物消耗ROS，这些聚合物递送雷帕霉素用于骨关节炎治疗。高级科学。（2023年）。在兔半月板不稳定模型中，线粒体功能的时间依赖性丧失先于进行性组织学软骨变性。

J. Orthop. Res. 35, 590–599 (2017).Article .

J.骨科。第35590-599号决议（2017年）。第[UNK]条。

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Bartell, L. R. et al. Mitoprotective therapy prevents rapid, strain-dependent mitochondrial dysfunction after articular cartilage injury. J. Orthop. Res. 38, 1257–1267 (2020).Article

Bartell，L.R。等人。线粒体保护疗法可预防关节软骨损伤后快速，应变依赖性线粒体功能障碍。J、 骨科。第381257-1267号决议（2020年）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Barrett-Jolley, R., Lewis, R., Fallman, R. & Mobasheri, A. The emerging chondrocyte channelome. Front. Physiol. 1, 135 (2010).Article

Barrett-Jolley，R.，Lewis，R.，Fallman，R。＆Mobasheri，A。新兴的软骨细胞通道组。正面。生理学。1135（2010）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Kefauver, J. M., Ward, A. B. & Patapoutian, A. Discoveries in structure and physiology of mechanically activated ion channels. Nature 587, 567–576 (2020).Article

。《自然》587567–576（2020）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Mobasheri, A. et al. The chondrocyte channelome: A narrative review. Jt. Bone Spine 86, 29–35 (2019).Article

Mobasheri，A。等人，《软骨细胞通道组：叙述性评论》。Jt公司。骨刺86,29-35（2019）。文章

CAS

中科院

Google Scholar

谷歌学者

Milner, P. I., Wilkins, R. J. & Gibson, J. S. The role of mitochondrial reactive oxygen species in pH regulation in articular chondrocytes. Osteoarthr. Cartil. 15, 735–742 (2007).Hopwood, B., Tsykin, A., Findlay, D. M. & Fazzalari, N. L. Microarray gene expression profiling of osteoarthritic bone suggests altered bone remodelling, WNT and transforming growth factor-beta/bone morphogenic protein signalling.

Milner，P.I.，Wilkins，R.J。＆Gibson，J.S。线粒体活性氧在关节软骨细胞pH调节中的作用。骨关节。卡蒂尔。15735-742（2007）。Hopwood，B.，Tsykin，A.，Findlay，D.M。和Fazzalari，N.L。骨关节炎骨的微阵列基因表达谱表明骨重塑，WNT和转化生长因子β/骨形态发生蛋白信号改变。

Arthritis Res. Ther. 9, R100 (2007).Donowitz, M. et al. NHERF family and NHE3 regulation. J. Physiol. 567, 3–11 (2005)Jiang, W. et al. Mechanisms linking mitochondrial mechanotransduction and chondrocyte biology in the pathogenesis of osteoarthritis. Ageing Res. Rev. 67, 101315 (2021).Article .

关节炎研究。9，R100（2007）。Donowitz，M。等人。NHERF家族和NHE3调控。J、 生理学。。《老龄化决议》第67版，第101315页（2021年）。文章。

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Chazotte, B. Labeling mitochondria with JC-1. Cold Spring Harb. Protoc. 2011, https://doi.org/10.1101/pdb.prot065490 (2011).Kim, H. et al. Correlation between PDZK1, Cdc37, Akt and breast cancer malignancy: the role of PDZK1 in cell growth through Akt stabilization by increasing and interacting with Cdc37.

Chazotte，B。用JC-1标记线粒体。冷泉兔。普罗托克。2011年，https://doi.org/10.1101/pdb.prot065490（2011年）。Kim，H。等人。PDZK1，Cdc37，Akt与乳腺癌恶性肿瘤之间的相关性：PDZK1通过增加Cdc37并与Cdc37相互作用来稳定Akt在细胞生长中的作用。

Mol. Med. 20, 270–279 (2014).Article .

摩尔医学杂志20270-279（2014）。文章。

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Bolduc, J. A., Collins, J. A. & Loeser, R. F. Reactive oxygen species, aging and articular cartilage homeostasis. Free Radic. Biol. Med 132, 73–82 (2019).Article

Bolduc，J.A.，Collins，J.A。＆Loeser，R.F。活性氧，衰老和关节软骨稳态。自由基。生物医学132,73-82（2019）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Chang, S. H. et al. Excessive mechanical loading promotes osteoarthritis through the gremlin-1-NF-κB pathway. Nat. Commun. 10, 1442 (2019).Article

Chang，S.H.等人。过度的机械负荷通过gremlin-1-NF-κB途径促进骨关节炎。国家公社。101442（2019）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Jiang, W. et al. Mechanical stress abnormalities promote chondrocyte senescence - The pathogenesis of knee osteoarthritis. Biomed. Pharmacother. 167, 115552 (2023).Article

Jiang，W.等人。机械应力异常促进软骨细胞衰老-膝关节骨性关节炎的发病机制。生物医学。药剂师。167115552（2023）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Qi, Y. et al. Long noncoding RNA PENG upregulates PDZK1 expression by sponging miR-15b to suppress clear cell renal cell carcinoma cell proliferation. Oncogene 39, 4404–4420 (2020).Article

Qi，Y。等人。长非编码RNA PENG通过海绵状miR-15b上调PDZK1表达以抑制透明细胞肾细胞癌细胞增殖。癌基因394404-4420（2020）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Zheng, J. et al. Low level of PDZ domain containing 1 (PDZK1) predicts poor clinical outcome in patients with clear cell renal cell carcinoma. EBioMedicine 15, 62–72 (2017).Article

Zheng，J。等人。低水平的含PDZ结构域1（PDZK1）预测透明细胞肾细胞癌患者的临床预后较差。EBioMedicine 15,62-72（2017）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Cha, B. et al. PDZ domain-dependent regulation of NHE3 protein by both internal Class II and C-terminal Class I PDZ-binding motifs. J. Biol. Chem. 292, 8279–8290 (2017).Article

Cha，B。等人。通过内部II类和C端I类PDZ结合基序对NHE3蛋白的PDZ结构域依赖性调节。J、 生物。化学。2928279-8290（2017）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Zhao, C. et al. Loss of PDZK1 expression activates PI3K/AKT signaling via PTEN phosphorylation in gastric cancer. Cancer Lett. 453, 107–121 (2019).Article

Zhao，C。等人。PDZK1表达的丧失通过胃癌中的PTEN磷酸化激活PI3K/AKT信号传导。癌症Lett。453107-121（2019）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Puchalska, P. & Crawford, P. A. Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics. Cell Metab. 25, 262–284 (2017).Article

Puchalska，P。＆Crawford，P.A。酮体在燃料代谢，信号传导和治疗中的多维作用。细胞代谢。25262-284（2017）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Bai, M. et al. LONP1 targets HMGCS2 to protect mitochondrial function and attenuate chronic kidney disease. EMBO Mol. Med. 15, e16581 (2023).Article

Bai，M。等人，LONP1靶向HMGCS2以保护线粒体功能并减轻慢性肾脏疾病。EMBO分子医学杂志15，e16581（2023）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Culley, K. L. et al. Mouse models of osteoarthritis: surgical model of post-traumatic osteoarthritis induced by destabilization of the medial meniscus. Methods Mol. Biol. 2221, 223–260 (2021).Article

Culley，K.L.等人，《骨关节炎的小鼠模型：由内侧半月板不稳定引起的创伤后骨关节炎的手术模型》。方法分子生物学。2221223-260（2021）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Tizro, P., Choi, C. & Khanlou, N. Sample preparation for transmission electron microscopy. Methods Mol. Biol. 1897, 417–424 (2019).Article

Tizro，P.，Choi，C。和Khanlou，N。透射电子显微镜的样品制备。方法分子生物学。1897417-424（2019）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Download referencesAcknowledgementsThis work was supported by grants from Natural Science Foundation of China grant No 82172491 (CN), National Natural Science Funds for Excellent Young Scholar No 82322044 (CN), National Key Research and Development Program of China (2022YFC3601902), Youth Talent Support Programme of Guangdong Provincial Association for Science and Technology (SKXRC202308) and State-funded postdoctoral researcher program No GZC20231062 (CN).Author informationAuthor notesThese authors contributed equally: Yan Shao, Hongbo Zhang, Hong GuanAuthors and AffiliationsDepartment of Joint Surgery, Center for Orthopedic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, ChinaYan Shao, Hongbo Zhang, Hong Guan, Chunyu Wu, Weizhong Qi, Lingfeng Yang, Jianbin Yin, Haiyan Zhang, Liangliang Liu, Yuheng Lu, Yitao Zhao, Chun Zeng, Xiaochun Bai & Daozhang CaiDepartment of Orthopedics, Orthopedic Hospital of Guangdong Province, Academy of Orthopedics Guangdong Province, The Third Affiliated Hospital of Southern Medical University, Guangzhou, ChinaYan Shao, Hongbo Zhang, Hong Guan, Chunyu Wu, Weizhong Qi, Lingfeng Yang, Jianbin Yin, Haiyan Zhang, Liangliang Liu, Yuheng Lu, Yitao Zhao, Chun Zeng, Xiaochun Bai & Daozhang CaiThe Third School of Clinical Medicine, Southern Medical University, Guangzhou, ChinaYan Shao, Hongbo Zhang, Hong Guan, Chunyu Wu, Weizhong Qi, Lingfeng Yang, Jianbin Yin, Haiyan Zhang, Liangliang Liu, Yuheng Lu, Yitao Zhao, Chun Zeng, Xiaochun Bai & Daozhang CaiOrthopedics Department, Qingyuan People’s Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, Guangdong, ChinaHong Guan & Guiqing WangDepartment of Cell Biology, School of Basic Medical Sciences, Southern Medical University.

下载参考文献致谢这项工作得到了中国自然科学基金82172491（CN），国家自然科学优秀青年基金82322044（CN），国家重点研究发展计划（2022YFC3601902），广东省科学技术协会青年人才支持计划（SKXRC202308）和国家资助博士后研究人员计划（GZC20231062（CN）的资助。作者信息作者注意到这些作者做出了同样的贡献：严绍，张洪波，张洪观作者和附属机构南方医科大学第三附属医院骨科，广州，中国严绍，张洪波，张洪观，吴春雨，吴伟忠，杨凌锋，尹建斌，张海燕，刘良良，卢玉恒，赵一涛，曾春春，白晓春，蔡道纯广东省骨科医院，广东省骨科学院，南方医科大学第三附属医院，广州，中国严绍，张洪波，张洪观，春雨吴伟忠、齐伟忠、杨凌锋、尹建斌、张海燕、刘良良、卢玉恒、赵一涛、曾春春、白晓春和蔡道章南方医科大学第三临床医学院，广州，邵燕、张洪波、洪冠、吴春雨、齐伟忠、杨凌锋、尹建斌，张海燕，刘良良，吕玉恒，赵一涛，曾春春，白晓春，蔡道章广州医科大学第六附属医院清远人民医院骨科，广东清远，中国关宏，王桂青南方医科大学基础医学院细胞生物学系。

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PubMed Google ScholarContributionsY.S, X.C.B and D.Z.C conceived the ideas for experimental designs, analyzed data and wrote the manuscript. Y.S and H.B.Z conducted the majority of the experiments and helped with manuscript preparation. H.G conducted the majority of the experiments and analyzed data.

PubMed谷歌学术贡献。S、 X.C.B和D.Z.C构思了实验设计的想法，分析了数据并撰写了手稿。Y、 S和H.B.Z进行了大多数实验，并帮助准备了手稿。H、 G进行了大部分实验并分析了数据。

C.Y.W, W.Z.Q and L.F.Y performed immunohistochemistry and immunofluorescence and confocal imaging. J.B.Y, Y.T.Z and H.Y.Z conducted cell cultures and western blot experiments. L.L.L, Y.H.L and S.Z collected human tissue samples. C.Z, G.Q.W and H.B.Z revised the manuscript. X.C.B and D.Z.C developed the concept, supervised the project and conceived the experiments.

C、 。J、 B.Y，Y.T.Z和H.Y.Z进行了细胞培养和蛋白质印迹实验。五十、 L.L，Y.H.L和S.Z收集人体组织样本。C、 Z，G.Q.W和H.B.Z修订了手稿。十、 C.B和D.Z.C开发了这个概念，监督了这个项目并构思了实验。

All authors approved the final version of the manuscript. D.Z.C accepted full responsibility for the finished work, had access to the data and controlled the decision to publish. Y.S, H.B.Z and H.G contributed equally to this work.Corresponding authorsCorrespondence to.

所有作者都批准了稿件的最终版本。D、 Z.C对完成的工作承担全部责任，可以访问数据并控制发布的决定。Y、 S，H.B.Z和H.G对这项工作做出了同样的贡献。

Xiaochun Bai or Daozhang Cai.Ethics declarations

小春白或道长菜。道德宣言

Competing interests

相互竞争的利益

The authors declare no competing interests.

作者声明没有利益冲突。

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Reprints and permissionsAbout this articleCite this articleShao, Y., Zhang, H., Guan, H. et al. PDZK1 protects against mechanical overload-induced chondrocyte senescence and osteoarthritis by targeting mitochondrial function.

转载和许可本文引用本文Shao，Y.，Zhang，H.，Guan，H。等人。PDZK1通过靶向线粒体功能来防止机械超负荷诱导的软骨细胞衰老和骨关节炎。

Bone Res 12, 41 (2024). https://doi.org/10.1038/s41413-024-00344-6Download citationReceived: 25 December 2023Revised: 29 April 2024Accepted: 12 May 2024Published: 17 July 2024DOI: https://doi.org/10.1038/s41413-024-00344-6Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

骨研究12,41（2024）。https://doi.org/10.1038/s41413-024-00344-6Download引文接收日期：2023年12月25日修订日期：2024年4月29日接受日期：2024年5月12日发布日期：2024年7月17日OI：https://doi.org/10.1038/s41413-024-00344-6Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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