AI Chat Paper
Note: Please note that the following content is generated by AMiner AI. SciOpen does not take any responsibility related to this content.
{{lang === 'zh_CN' ? '文章概述' : 'Summary'}}
{{lang === 'en_US' ? '中' : 'Eng'}}
Chat more with AI
Powered by AMiner. Clicking this button will take you away from SciOpen.
Home Bone Research Article
PDF (4.6 MB)
Cite
EndNote(RIS) BibTeX
Collect
Submit Manuscript AI Chat Paper
Show Outline
Outline
Show full outline
Hide outline
Outline
Show full outline
Hide outline
Review | Open Access

Current understanding of osteoarthritis pathogenesis and relevant new approaches

Liping Tong1, Huan Yu1,2, Xingyun Huang1,2, Jie Shen3, Guozhi Xiao4, Lin Chen5, Huaiyu Wang6, Lianping Xing7, Di Chen1,2( )
Research Center for Computer-aided Drug Discovery, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518005, China
Faculty of Pharmaceutical Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
Department of Orthopedic Surgery, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA
School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China
Department of Wound Repair and Rehabilitation, State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
Research Center for Human Tissues and Organs Degeneration, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
Department of Pathology and Laboratory of Medicine, Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY 14642, USA
Show Author Information

Abstract

Osteoarthritis (OA) is the most common degenerative joint disease that causes painful swelling and permanent damage to the joints in the body. The molecular mechanisms of OA are currently unknown. OA is a heterogeneous disease that affects the entire joint, and multiple tissues are altered during OA development. To better understand the pathological mechanisms of OA, new approaches, methods, and techniques need to be used to understand OA pathogenesis. In this review, we first focus on the epigenetic regulation of OA, with a particular focus on DNA methylation, histone modification, and microRNA regulation, followed by a summary of several key mediators in OA-associated pain. We then introduce several innovative techniques that have been and will continue to be used in the fields of OA and OA-associated pain, such as CRISPR, scRNA sequencing, and lineage tracing. Next, we discuss the timely updates concerning cell death regulation in OA pathology, including pyroptosis, ferroptosis, and autophagy, as well as their individual roles in OA and potential molecular targets in treating OA. Finally, our review highlights new directions on the role of the synovial lymphatic system in OA. An improved understanding of OA pathogenesis will aid in the development of more specific and effective therapeutic interventions for OA.

References

1

Chen, D. Osteoarthritis: a complicated joint disease requiring extensive studies with multiple approaches. J. Orthop. Translat. 32, 130 (2022).
Crossref Google Scholar
2

Chen, D. et al. Osteoarthritis: toward a comprehensive understanding of pathological mechanism. Bone Res. 5, 16044 (2017).
Crossref Google Scholar
3

Li, Y., Xie, W., Xiao, W. & Dou, D. Progress in osteoarthritis research by the National Natural Science Foundation of China. Bone Res. 10, 41 (2022).
Crossref Google Scholar
4

Sun, A. R. et al. Cartilage tissue engineering for obesity-induced osteoarthritis: physiology, challenges, and future prospects. J. Orthop. Translat. 26, 3–15 (2021).
Crossref Google Scholar
5

Wu, X. H., Lai, Y. M., Cao, H. L. & Xiao, G. Z. Kindlin-2 preserves integrity of the articular cartilage to protect against osteoarthritis. J. Bone Min. Res. 37, 45–46 (2022).
Crossref Google Scholar
6

Wen, C. & Xiao, G. Advances in osteoarthritis research in 2021 and beyond. J. Orthop. Translat. 32, A1–A2 (2022).
Crossref Google Scholar
7

GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 392, 1789–1858 (2018).
Crossref Google Scholar
8

Li, J., Wang, Y., Chen, D. & Liu-Bryan, R. Oral administration of berberine limits post-traumatic osteoarthritis development and associated pain via AMP-activated protein kinase (AMPK) in mice. Osteoarthr. Cartil. 30, 160–171 (2022).
Crossref Google Scholar
9

Li, J. et al. Metformin limits osteoarthritis development and progression through activation of AMPK signalling. Ann. Rheum. Dis. 79, 635–645 (2020).
Crossref Google Scholar
10

Lu, K. et al. Molecular signaling in temporomandibular joint osteoarthritis. J. Orthop. Translat. 32, 21–27 (2022).
Crossref Google Scholar
11

Katz, J. N., Arant, K. R. & Loeser, R. F. Diagnosis and treatment of hip and knee osteoarthritis: a review. JAMA 325, 568–578 (2021).
Crossref Google Scholar
12

Ni, R., Guo, X. E., Yan, C. & Wen, C. Hemodynamic stress shapes subchondral bone in osteoarthritis: An emerging hypothesis. J. Orthop. Translat. 32, 85–90 (2022).
Crossref Google Scholar
13

McHugh, J. Osteoarthritis risk factors differ between sexes. Nat. Rev. Rheumatol. 17, 312 (2021).
Crossref Google Scholar
14

Huang, W., Ong, T. Y., Fu, S. C. & Yung, S. H. Prevalence of patellofemoral joint osteoarthritis after anterior cruciate ligament injury and associated risk factors: a systematic review. J. Orthop. Translat. 22, 14–25 (2020).
Crossref Google Scholar
15

Fang, L. et al. Defining disease progression in Chinese mainland people: association between bone mineral density and knee osteoarthritis. J. Orthop. Translat. 26, 39–44 (2021).
Crossref Google Scholar
16

Hunter, D. J. & Bierma-Zeinstra, S. Osteoarthritis. Lancet 393, 1745–1759 (2019).
Crossref Google Scholar
17

Chen, L. et al. Pathogenesis and clinical management of obesity-related knee osteoarthritis: Impact of mechanical loading. J. Orthop. Translat. 24, 66–75 (2020).
Crossref Google Scholar
18

Meurot, C. et al. Targeting the GLP-1/GLP-1R axis to treat osteoarthritis: a new opportunity? J. Orthop. Translat. 32, 121–129 (2022).
Crossref Google Scholar
19

Chen, D., Kim, D. J., Shen, J., Zou, Z. & O’Keefe, R. J. Runx2 plays a central role in Osteoarthritis development. J. Orthop. Translat. 23, 132–139 (2020).
Crossref Google Scholar
20

Yu, H., Huang, T., Lu, W. W., Tong, L. & Chen, D. Osteoarthritis Pain. Int. J. Mol. Sci. 23, 4642 (2022).
Crossref Google Scholar
21

Li, J., Ma, K., Yi, D., Oh, C. D. & Chen, D. Nociceptive behavioural assessments in mouse models of temporomandibular joint disorders. Int. J. Oral Sci. 12, 26 (2020).
Crossref Google Scholar
22

Zhou, F. et al. Associations of osteoclastogenesis and nerve growth in subchondral bone marrow lesions with clinical symptoms in knee osteoarthritis. J. Orthop. Translat. 32, 69–76 (2022).
Crossref Google Scholar
23

Yang, J. et al. Targeting cell death: pyroptosis, ferroptosis, apoptosis and necroptosis in osteoarthritis. Front. Cell Dev. Biol. 9, 789948 (2021).
Crossref Google Scholar
24

Cao, M., Ong, M. T. Y., Yung, P. S. H., Tuan, R. S. & Jiang, Y. Role of synovial lymphatic function in osteoarthritis. Osteoarthr. Cartil. (2022).
Crossref Google Scholar
25

Wang, W. et al. Attenuated joint tissue damage associated with improved synovial lymphatic function following treatment with bortezomib in a mouse model of experimental posttraumatic osteoarthritis. Arthritis Rheumatol. 71, 244–257 (2019).
Crossref Google Scholar
26

Yu, H. et al. Morroniside attenuates apoptosis and pyroptosis of chondrocytes and ameliorates osteoarthritic development by inhibiting NF-κB signaling. J. Ethnopharmacol. 266, 113447 (2021).
Crossref Google Scholar
27

Simon, T. C. & Jeffries, M. A. The epigenomic landscape in osteoarthritis. Curr. Rheumatol. Rep. 19, 30 (2017).
Crossref Google Scholar
28

Zhang, M. & Wang, J. Epigenetics and osteoarthritis. Genes Dis. 2, 69–75 (2015).
Crossref Google Scholar
29

Roach, H. I. & Aigner, T. DNA methylation in osteoarthritic chondrocytes: a new molecular target. Osteoarthr. Cartil. 15, 128–137 (2007).
Crossref Google Scholar
30

Miranda-Duarte, A. DNA methylation in osteoarthritis: current status and therapeutic implications. Open Rheumatol. J. 12, 37–49 (2018).
Crossref Google Scholar
31

Morris, M. J. & Monteggia, L. M. Role of DNA methylation and the DNA methyltransferases in learning and memory. Dialogues Clin. Neurosci. 16, 359–371 (2014).
Crossref Google Scholar
32

Li, E., Bestor, T. H. & Jaenisch, R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69, 915–926 (1992).
Crossref Google Scholar
33

Okano, M., Bell, D. W., Haber, D. A. & Li, E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99, 247–257 (1999).
Crossref Google Scholar
34

Jeffries, M. A. et al. Genome-wide DNA methylation study identifies significant epigenomic changes in osteoarthritic cartilage. Arthritis Rheumatol. 66, 2804–2815 (2014).
Crossref Google Scholar
35

Raman, S., FitzGerald, U. & Murphy, J. M. Interplay of inflammatory mediators with epigenetics and cartilage modifications in osteoarthritis. Front. Bioeng. Biotechnol. 6, 22 (2018).
Crossref Google Scholar
36
Chen, D., Shen, J. & Hui, T. Epigenetic and microRNA regulation during osteoarthritis development. F1000Res. 4, F1000 Faculty Rev−1092 (2015).
Crossref
37

Cheung, K. S., Hashimoto, K., Yamada, N. & Roach, H. I. Expression of ADAMTS-4 by chondrocytes in the surface zone of human osteoarthritic cartilage is regulated by epigenetic DNA de-methylation. Rheumatol. Int. 29, 525–534 (2009).
Crossref Google Scholar
38

Hashimoto, K., Oreffo, R. O., Gibson, M. B., Goldring, M. B. & Roach, H. I. DNA demethylation at specific CpG sites in the IL1B promoter in response to inflammatory cytokines in human articular chondrocytes. Arthritis Rheumatol. 60, 3303–3313 (2009).
Crossref Google Scholar
39

Roach, H. I. et al. Association between the abnormal expression of matrix-degrading enzymes by human osteoarthritic chondrocytes and demethylation of specific CpG sites in the promoter regions. Arthritis Rheumtol. 52, 3110–3124 (2005).
Crossref Google Scholar
40

Shen, J., Abu-Amer, Y., O’Keefe, R. J. & McAlinden, A. Inflammation and epigenetic regulation in osteoarthritis. Connect. Tissue Res. 58, 49–63 (2017).
Crossref Google Scholar
41

Zimmermann, P. et al. Correlation of COL10A1 induction during chondrogenesis of mesenchymal stem cells with demethylation of two CpG sites in the COL10A1 promoter. Arthritis Rheumatol. 58, 2743–2753 (2008).
Crossref Google Scholar
42

Tan, L. & Shi, Y. G. Tet family proteins and 5-hydroxymethylcytosine in development and disease. Development 139, 1895–1902 (2012).
Crossref Google Scholar
43

Andrés, M. D. et al. Loss of methylation in CpG sites in the NF-κB enhancer elements of inducible nitric oxide synthase is responsible for gene induction in human articular chondrocytes. Arthritis Rheumtol. 65, 732–742 (2014).
Crossref Google Scholar
44

Lin, X. et al. Genome-wide analysis of aberrant methylation of enhancer DNA in human osteoarthritis. BMC Med. Genomics 13, 1 (2020).
Crossref Google Scholar
45

Whalen, S., Truty, R. M. & Pollard, K. S. Enhancer-promoter interactions are encoded by complex genomic signatures on looping chromatin. Nat. Genet. 48, 488–496 (2016).
Crossref Google Scholar
46

Zhu, X. et al. PPARgamma preservation via promoter demethylation alleviates osteoarthritis in mice. Ann. Rheum. Dis. 78, 1420–1429 (2019).
Crossref Google Scholar
47

Deng, Z. et al. Losartan protects against osteoarthritis by repressing the TGF-beta1 signaling pathway via upregulation of PPARgamma. J. Orthop. Translat. 29, 30–41 (2021).
Crossref Google Scholar
48

Shen, J. et al. DNA methyltransferase 3b regulates articular cartilage homeostasis by altering metabolism. JCI Insight. 2, e93612 (2017).
Crossref Google Scholar
49

Zhou, Y. et al. Epigenetic and therapeutic implications of dnmt3b in temporomandibular joint osteoarthritis. Am. J. Transl. Res. 11, 1736–1747 (2019).
Google Scholar
50

Blanco, F. J. & Rego-Perez, I. Editorial: Is it time for epigenetics in osteoarthritis? Arthritis Rheumatol. 66, 2324–2327 (2014).
Crossref Google Scholar
51

Kim, H., Kang, D., Cho, Y. & Kim, J. H. Epigenetic regulation of chondrocyte catabolism and anabolism in osteoarthritis. Mol. Cells 38, 677–684 (2015).
Crossref Google Scholar
52

Bradley, E. W., Carpio, L. R., van Wijnen, A. J., McGee-Lawrence, M. E. & Westendorf, J. J. Histone deacetylases in bone development and skeletal disorders. Physiol. Rev. 95, 1359–1381 (2015).
Crossref Google Scholar
53

Cao, K. et al. Decreased histone deacetylase 4 is associated with human osteoarthritis cartilage degeneration by releasing histone deacetylase 4 inhibition of runt-related transcription factor-2 and increasing osteoarthritis-related genes: a novel mechanism of human osteoarthritis cartilage degeneration. Arthritis Res. Ther. 16, 491 (2014).
Crossref Google Scholar
54

El Mansouri, F. et al. Lysine-specific demethylase 1-mediated demethylation of histone H3 lysine 9 contributes to interleukin 1β-induced microsomal prostaglandin E synthase 1 expression in human osteoarthritic chondrocytes. Arthritis Res. Ther. 16, R113 (2014).
Crossref Google Scholar
55

El Mansouri, F. E. et al. Contribution of H3K4 methylation by SET-1A to interleukin-1-induced cyclooxygenase 2 and inducible nitric oxide synthase expression in human osteoarthritis chondrocytes. Arthritis Rheumatol. 63, 168–179 (2011).
Crossref Google Scholar
56

Higashiyama, R. et al. Correlation between MMP-13 and HDAC7 expression in human knee osteoarthritis. Mod. Rheumatol. 20, 11–17 (2010).
Crossref Google Scholar
57

Kim, K. I., Park, Y. S. & Im, G. I. Changes in the epigenetic status of the SOX-9 promoter in human osteoarthritic cartilage. J. Bone Miner. Res. 28, 1050–1060 (2013).
Crossref Google Scholar
58

Hong, S., Derfoul, A., Pereira-Mouries, L. & Hall, D. J. A novel domain in histone deacetylase 1 and 2 mediates repression of cartilage-specific genes in human chondrocytes. FASEB J. 23, 3539–3552 (2009).
Crossref Google Scholar
59

Huber, L. C. et al. Histone deacetylase/acetylase activity in total synovial tissue derived from rheumatoid arthritis and osteoarthritis patients. Arthritis Rheumatol. 56, 1087–1093 (2007).
Crossref Google Scholar
60

Huh, Y. H., Ryu, J. H. & Chun, J. S. Regulation of type Ⅱ collagen expression by histone deacetylase in articular chondrocytes. J. Biol. Chem. 282, 17123–17131 (2007).
Crossref Google Scholar
61

Lu, J., Sun, Y., Ge, Q., Teng, H. & Jiang, Q. Histone deacetylase 4 alters cartilage homeostasis in human osteoarthritis. BMC Musculoskelet. Disord. 15, 438 (2014).
Crossref Google Scholar
62

Chang, L. H., Chen, C. H., Wu, S. C., Chang, J. K. & Ho, M. L. Cyclooxygenase-2 regulates PTHrP transcription in human articular chondrocytes and is involved in the pathophysiology of osteoarthritis in rats. J. Orthop. Translat. 30, 16–30 (2021).
Crossref Google Scholar
63

Im, G. I. & Choi, Y. J. Epigenetics in osteoarthritis and its implication for future therapeutics. Expert Opin. Biol. Ther. 13, 713–721 (2013).
Crossref Google Scholar
64

Cai, D., Yin, S., Yang, J., Jiang, Q. & Cao, W. Histone deacetylase inhibition activates Nrf2 and protects against osteoarthritis. Arthritis Res. Ther. 17, 269 (2015).
Crossref Google Scholar
65

Culley, K. L. et al. Class Ⅰ histone deacetylase inhibition modulates metalloproteinase expression and blocks cytokine-induced cartilage degradation. Arthritis Rheumatol. 65, 1822–1830 (2013).
Crossref Google Scholar
66

Khan, N. M. & Haqqi, T. M. Epigenetics in osteoarthritis: potential of HDAC inhibitors as therapeutics. Pharmacol. Res. 128, 73–79 (2018).
Crossref Google Scholar
67

Makki, M. S. & Haqqi, T. M. Histone deacetylase inhibitor vorinostat (SAHA) suppresses IL-1beta-induced matrix metallopeptidase-13 expression by inhibiting IL-6 in osteoarthritis chondrocyte. Am. J. Pathol. 186, 2701–2708 (2016).
Crossref Google Scholar
68

Wang, X., Song, Y., Jacobi, J. L. & Tuan, R. S. Inhibition of histone deacetylases antagonized FGF2 and IL-1beta effects on MMP expression in human articular chondrocytes. Growth Factors 27, 40–49 (2009).
Crossref Google Scholar
69

Zhong, H. M., Ding, Q. H., Chen, W. P. & Luo, R. B. Vorinostat, a HDAC inhibitor, showed anti-osteoarthritic activities through inhibition of iNOS and MMP expression, p38 and ERK phosphorylation and blocking NF-kappaB nuclear translocation. Int. Immunopharmacol. 17, 329–335 (2013).
Crossref Google Scholar
70

Liu, T. F., Yoza, B. K., El Gazzar, M., Vachharajani, V. T. & McCall, C. E. NAD+-dependent SIRT1 deacetylase participates in epigenetic reprogramming during endotoxin tolerance. J. Biol. Chem. 286, 9856–9864 (2011).
Crossref Google Scholar
71

Matsuzaki, T. et al. Disruption of Sirt1 in chondrocytes causes accelerated progression of osteoarthritis under mechanical stress and during ageing in mice. Ann. Rheum. Dis. 73, 1397–1404 (2014).
Crossref Google Scholar
72

Moon, M. H. et al. SIRT1, a class Ⅲ histone deacetylase, regulates TNF-alpha-induced inflammation in human chondrocytes. Osteoarthr. Cartil. 21, 470–480 (2013).
Crossref Google Scholar
73

Takayama, K. et al. SIRT1 regulation of apoptosis of human chondrocytes. Arthritis Rheumatol. 60, 2731–2740 (2009).
Crossref Google Scholar
74

Matsushita, T. et al. The overexpression of SIRT1 inhibited osteoarthritic gene expression changes induced by interleukin-1beta in human chondrocytes. J. Orthop. Res. 31, 531–537 (2013).
Crossref Google Scholar
75

Deng, Z. et al. The role of sirtuin 1 and its activator, resveratrol in osteoarthritis. Biosci. Rep. 39, BSR20190189 (2019).
Crossref Google Scholar
76

Kim, H. J., Braun, H. J. & Dragoo, J. L. The effect of resveratrol on normal and osteoarthritic chondrocyte metabolism. Bone Jt. Res. 3, 51–59 (2014).
Crossref Google Scholar
77

Lei, M. et al. Resveratrol inhibits interleukin 1beta-mediated inducible nitric oxide synthase expression in articular chondrocytes by activating SIRT1 and thereby suppressing nuclear factor-kappaB activity. Eur. J. Pharmacol. 674, 73–79 (2012).
Crossref Google Scholar
78

Lim, H. D. et al. Cytoprotective and anti-inflammatory effects of melatonin in hydrogen peroxide-stimulated CHON-001 human chondrocyte cell line and rabbit model of osteoarthritis via the SIRT1 pathway. J. Pineal Res. 53, 225–237 (2012).
Crossref Google Scholar
79

Marouf, B. H., Hussain, S. A., Ali, Z. S. & Ahmmad, R. S. Resveratrol supplementation reduces pain and inflammation in knee osteoarthritis patients treated with meloxicam: a randomized placebo-controlled study. J. Med. Food (2018).
Crossref Google Scholar
80

Nishida, K. et al. Intraperitoneal injection of the SIRT1 activator SRT1720 attenuates the progression of experimental osteoarthritis in mice. Bone Jt. Res. 7, 252–262 (2018).
Crossref Google Scholar
81

Krol, J., Loedige, I. & Filipowicz, W. The widespread regulation of microRNA biogenesis, function and decay. Nat. Rev. Genet. 11, 597–610 (2010).
Crossref Google Scholar
82

Du, X. F. et al. Role of the miR-133a-5p/FBXO6 axis in the regulation of intervertebral disc degeneration. J. Orthop. Translat. 29, 123–133 (2021).
Crossref Google Scholar
83

MacFarlane, L. A. & Murphy, P. R. MicroRNA: biogenesis, function and role in cancer. Curr. Genomics 11, 537–561 (2010).
Crossref Google Scholar
84

Friedman, R. C., Farh, K. H., Burge, C. B. & Bartel, D. P. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 19, 92–105 (2008).
Crossref Google Scholar
85

Benz, F., Roy, S., Trautwein, C., Roderburg, C. & Luedde, T. Circulating MicroRNAs as Biomarkers for Sepsis. Int. J. Mol. Sci. 17, 78 (2016).
Crossref Google Scholar
86

Coutinho de Almeida, R. et al. RNA sequencing data integration reveals an miRNA interactome of osteoarthritis cartilage. Ann. Rheum. Dis. 78, 270–277 (2019).
Crossref Google Scholar
87

Yoshida, C. A. et al. Runx2 and Runx3 are essential for chondrocyte maturation, and Runx2 regulates limb growth through induction of Indian hedgehog. Gene Dev. 18, 952–963 (2004).
Crossref Google Scholar
88

Kamekura, S. et al. Contribution of runt-related transcription factor 2 to the pathogenesis of osteoarthritis in mice after induction of knee joint instability. Arthritis Rheumatol. 54, 2462–2470 (2010).
Crossref Google Scholar
89

Liao, L. et al. Deletion of Runx2 in articular chondrocytes decelerates the progression of DMM-induced osteoarthritis in adult mice. Sci. Rep. 7, 2371 (2017).
Crossref Google Scholar
90

Huang, J., Zhao, L., Xing, L. & Chen, D. MicroRNA-204 regulates Runx2 protein expression and mesenchymal progenitor cell differentiation. Stem Cells 28, 357–364 (2010).
Crossref Google Scholar
91

Huang, J. et al. The microRNAs miR-204 and miR-211 maintain joint homeostasis and protect against osteoarthritis progression. Nat. Commun. 10, 2876 (2019).
Crossref Google Scholar
92

Zhu, S. et al. Coupling factors and exosomal packaging microRNAs involved in the regulation of bone remodelling. Biol. Rev. Camb. Philos. Soc. 93, 469–480 (2018).
Crossref Google Scholar
93

Nakamura, A. et al. microRNA-181a-5p antisense oligonucleotides attenuate osteoarthritis in facet and knee joints. Ann. Rheum. Dis. 78, 111–121 (2019).
Crossref Google Scholar
94

Wu, D. et al. Brain endothelial miR-146a negatively modulates T-cell adhesion through repressing multiple targets to inhibit NF-κB activation. J. Cereb. Blood Flow. Metab. 35, 412–423 (2015).
Crossref Google Scholar
95

Zhong, G. et al. miRNA-335-5p relieves chondrocyte inflammation by activating autophagy in osteoarthritis. Life Sci. 226, 164–172 (2019).
Crossref Google Scholar
96

Ding, Y., Wang, L., Zhao, Q., Wu, Z. & Kong, L. MicroRNA93 inhibits chondrocyte apoptosis and inflammation in osteoarthritis by targeting the TLR4/NF-κB signaling pathway. Int. J. Mol. Med. 43, 779–790 (2019).
Crossref Google Scholar
97

Bjurstrom, M. F. et al. Central nervous system monoaminergic activity in hip osteoarthritis patients with disabling pain: associations with pain severity and central sensitization. Pain. Rep. 7, e988 (2022).
Crossref Google Scholar
98

Gungor Demir, U., Demir, A. N. & Toraman, N. F. Neuropathic pain in knee osteoarthritis. Adv. Rheumatol. 61, 67 (2021).
Crossref Google Scholar
99

Graven-Nielsen, T., Wodehouse, T., Langford, R. M., Arendt-Nielsen, L. & Kidd, B. L. Normalization of widespread hyperesthesia and facilitated spatial summation of deep-tissue pain in knee osteoarthritis patients after knee replacement. Arthritis Rheumatol. 64, 2907–2916 (2012).
Crossref Google Scholar
100

Manni, L. et al. Nerve growth factor: basic studies and possible therapeutic applications. Growth Factors 31, 115–122 (2013).
Crossref Google Scholar
101

Hirose, M., Kuroda, Y. & Murata, E. NGF/TrkA signaling as a therapeutic target for pain. Pain Pract. 16, 175–182 (2016).
Crossref Google Scholar
102

Norman, B. H. & McDermott, J. S. Targeting the nerve growth factor (NGF) pathway in drug discovery. Potential applications to new therapies for chronic pain. J. Med. Chem. 60, 66–88 (2017).
Crossref Google Scholar
103

Takatori, M., Kuroda, Y. & Hirose, M. Local anesthetics suppress nerve growth factor-mediated neurite outgrowth by inhibition of tyrosine kinase activity of TrkA. Anesth. Analg. 102, 462–467 (2006).
Crossref Google Scholar
104

Dakin, P. et al. The efficacy, tolerability, and joint safety of fasinumab in osteoarthritis pain: a phase Ⅱb/Ⅲ double-blind, placebo-controlled, randomized clinical trial. Arthritis Rheumatol. 71, 1824–1834 (2019).
Crossref Google Scholar
105

Berenbaum, F. et al. Subcutaneous tanezumab for osteoarthritis of the hip or knee: efficacy and safety results from a 24-week randomised phase Ⅲ study with a 24-week follow-up period. Ann. Rheum. Dis. 79, 800–810 (2020).
Crossref Google Scholar
106

Kim, J. S. et al. Characterization of degenerative human facet joints and facet joint capsular tissues. Osteoarthr. Cartil. 23, 2242–2251 (2015).
Crossref Google Scholar
107

Seidel, M. F., Netzer, C., Chobaz, V., Hugle, T. & Geurts, J. Localization of nerve growth factor expression to structurally damaged cartilaginous tissues in human lumbar facet joint osteoarthritis. Front. Immunol. 13, 783076 (2022).
Crossref Google Scholar
108

Dakin, P. et al. Efficacy and safety of fasinumab in patients with chronic low back pain: a phase Ⅱ/Ⅲ randomised clinical trial. Ann. Rheum. Dis. 80, 509–517 (2020).
Crossref Google Scholar
109

Andoh, T., Asakawa, Y. & Kuraishi, Y. Non-myelinated C-fibers, but not myelinated A-fibers, elongate into the epidermis in dry skin with itch. Neurosci. Lett. 672, 84–89 (2018).
Crossref Google Scholar
110

Eftekhari, S., Warfvinge, K., Blixt, F. W. & Edvinsson, L. Differentiation of nerve fibers storing CGRP and CGRP receptors in the peripheral trigeminovascular system. J. Pain 14, 1289–1303 (2013).
Crossref Google Scholar
111

Melo-Carrillo, A. et al. Fremanezumab-A humanized monoclonal anti-CGRP antibody-inhibits thinly myelinated (Adelta) but not unmyelinated (C) menin.geal nociceptors. J. Neurosci. 37, 10587–10596 (2017).
Crossref Google Scholar
112

Buma, P., Elmans, L., Van Den Berg, W. B. & Schrama, L. H. Neurovascular plasticity in the knee joint of an arthritic mouse model. Anat. Rec. 260, 51–61 (2000).
Crossref Google Scholar
113

Dong, T. et al. Calcitonin gene-related peptide can be selected as a predictive biomarker on progression and prognosis of knee osteoarthritis. Int. Orthop. 39, 1237–1243 (2015).
Crossref Google Scholar
114

Benschop, R. J. et al. Development of a novel antibody to calcitonin gene-related peptide for the treatment of osteoarthritis-related pain. Osteoarthr. Cartil. 22, 578–585 (2014).
Crossref Google Scholar
115

Jin, Y. et al. CGRP blockade by galcanezumab was not associated with reductions in signs and symptoms of knee osteoarthritis in a randomized clinical trial. Osteoarthr. Cartil. 26, 1609–1618 (2018).
Crossref Google Scholar
116

Mogil, J. S. Qualitative sex differences in pain processing: emerging evidence of a biased literature. Nat. Rev. Neurosci. 21, 353–365 (2020).
Crossref Google Scholar
117

Halievski, K., Ghazisaeidi, S. & Salter, M. W. Sex-dependent mechanisms of chronic pain: a focus on microglia and P2X4R. J. Pharmacol. Exp. Ther. 375, 202–209 (2020).
Crossref Google Scholar
118

Uchida, K. et al. Differential synovial CGRP/RAMP1 expression in men and women with knee osteoarthritis. Cureus. 13, e15483 (2021).
Crossref Google Scholar
119

Miller, R. J., Jung, H., Bhangoo, S. K. & White, F. A. Cytokine and chemokine regulation of sensory neuron function. Handb. Exp. Pharmacol. 194, 417–449 (2009).
Crossref Google Scholar
120

White, F. A., Feldman, P. & Miller, R. J. Chemokine signaling and the management of neuropathic pain. Mol. Interv. 9, 188–195 (2009).
Crossref Google Scholar
121

Decosterd, I. & Woolf, C. J. Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain 87, 149–158 (2000).
Crossref Google Scholar
122

White, F. A. & Miller, R. J. Insights into the regulation of chemokine receptors by molecular signaling pathways: Functional roles in neuropathic pain. Brain Behav. Immun. 24, 859–865 (2010).
Crossref Google Scholar
123

Miller, R. E. et al. CCR2 chemokine receptor signaling mediates pain in experimental osteoarthritis. Proc. Natl. Acad. Sci. USA 109, 20602–20607 (2012).
Crossref Google Scholar
124

Griffith, J. W., Sokol, C. L. & Luster, A. D. Chemokines and chemokine receptors: positioning cells for host defense and immunity. Annu. Rev. Immunol. 32, 659–702 (2014).
Crossref Google Scholar
125

Raghu, H. et al. CCL2/CCR2, but not CCL5/CCR5, mediates monocyte recruitment, inflammation and cartilage destruction in osteoarthritis. Ann. Rheum. Dis. 76, 914–922 (2017).
Crossref Google Scholar
126

Ishihara, S. et al. The role of intra-articular neuronal CCR2 receptors in knee joint pain associated with experimental osteoarthritis in mice. Arthritis Res. Ther. 23, 103 (2021).
Crossref Google Scholar
127

Guan, Z. et al. Injured sensory neuron-derived CSF1 induces microglial proliferation and DAP12-dependent pain. Nat. Neurosci. 19, 94–101 (2016).
Crossref Google Scholar
128

Zhang, Z. J., Jiang, B. C. & Gao, Y. J. Chemokines in neuron-glial cell interaction and pathogenesis of neuropathic pain. Cell. Mol. Life Sci. 74, 3275–3291 (2017).
Crossref Google Scholar
129

Zhuang, Z. Y. et al. Role of the CX3CR1/p38 MAPK pathway in spinal microglia for the development of neuropathic pain following nerve injury-induced cleavage of fractalkine. Brain Behav. Immun. 21, 642–651 (2007).
Crossref Google Scholar
130

Grace, P. M., Hutchinson, M. R., Maier, S. F. & Watkins, L. R. Pathological pain and the neuroimmune interface. Nat. Rev. Immunol. 14, 217–231 (2014).
Crossref Google Scholar
131

Chen, G., Zhang, Y. Q., Qadri, Y. J., Serhan, C. N. & Ji, R. R. Microglia in pain: detrimental and protective roles in pathogenesis and resolution of pain. Neuron 100, 1292–1311 (2018).
Crossref Google Scholar
132

Watkins, L. R. et al. Glia as the “bad guys”: implications for improving clinical pain control and the clinical utility of opioids. Brain Behav. Immun. 21, 131–146 (2007).
Crossref Google Scholar
133

Chavan, S. S., Pavlov, V. A. & Tracey, K. J. Mechanisms and therapeutic relevance of neuro-immune communication. Immunity 46, 927–942 (2017).
Crossref Google Scholar
134

Scholz, J. & Woolf, C. J. The neuropathic pain triad: neurons, immune cells and glia. Nat. Neurosci. 10, 1361–1368 (2007).
Crossref Google Scholar
135

Ji, R. R., Chamessian, A. & Zhang, Y. Q. Pain regulation by non-neuronal cells and inflammation. Science 354, 572–577 (2016).
Crossref Google Scholar
136

Kawasaki, Y., Zhang, L., Cheng, J. K. & Ji, R. R. Cytokine mechanisms of central sensitization: distinct and overlapping role of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in regulating synaptic and neuronal activity in the superficial spinal cord. J. Neurosci. 28, 5189–5194 (2008).
Crossref Google Scholar
137

Wojdasiewicz, P., Poniatowski, L. A. & Szukiewicz, D. The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of osteoarthritis. Mediators Inflamm. 2014, 561459 (2014).
Crossref Google Scholar
138

Kloppenburg, M. et al. Etanercept in patients with inflammatory hand osteoarthritis (EHOA): a multicentre, randomised, double-blind, placebo-controlled trial. Ann. Rheum. Dis. 77, 1757–1764 (2018).
Crossref Google Scholar
139

Aitken, D. et al. A randomised double-blind placebo-controlled crossover trial of HUMira (adalimumab) for erosive hand OsteoaRthritis - the HUMOR trial. Osteoarthr. Cartil. 26, 880–887 (2018).
Crossref Google Scholar
140

Fu, W. et al. 14-3-3 epsilon is an intracellular component of TNFR2 receptor complex and its activation protects against osteoarthritis. Ann. Rheum. Dis. 80, 1615–1627 (2021).
Crossref Google Scholar
141

Pickar-Oliver, A. & Gersbach, C. A. The next generation of CRISPR-Cas technologies and applications. Nat. Rev. Mol. Cell Biol. 20, 490–507 (2019).
Crossref Google Scholar
142

Barrangou, R. et al. CRISPR provides acquired resistance against viruses in prokaryotes. Science 315, 1709–1712 (2007).
Crossref Google Scholar
143

Makarova, K. S. et al. An updated evolutionary classification of CRISPR–Cas systems. Nat. Rev. Microbiol 13, 722–736 (2015).
Crossref Google Scholar
144

Koonin, E. V., Makarova, K. S. & Zhang, F. Diversity, classification and evolution of CRISPR-Cas systems. Curr. Opin. Microbiol. 37, 67–78 (2017).
Crossref Google Scholar
145

Shmakov, S. et al. Diversity and evolution of class 2 CRISPR-Cas systems. Nat. Rev. Microbiol 15, 169–182 (2017).
Crossref Google Scholar
146

Hsu, P. D., Lander, E. S. & Zhang, F. Development and applications of CRISPR-Cas9 for genome engineering. Cell 157, 1262–1278 (2014).
Crossref Google Scholar
147

Jinek, M. et al. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337, 816–821 (2012).
Crossref Google Scholar
148

Wyman, C. & Kanaar, R. DNA double-strand break repair: all’s well that ends well. Annu. Rev. Genet. 40, 363–383 (2006).
Crossref Google Scholar
149

Bibikova, M., Golic, M., Golic, K. G. & Carroll, D. Targeted chromosomal cleavage and mutagenesis in Drosophila using zinc-finger nucleases. Genetics 161, 1169–1175 (2002).
Crossref Google Scholar
150

Cong, L. et al. Multiplex genome engineering using CRISPR/Cas systems. Science 339, 819–823 (2013).
Crossref Google Scholar
151

Gutschner, T., Haemmerle, M., Genovese, G., Draetta, G. F. & Chin, L. Post-translational regulation of Cas9 during G1 enhances homology-directed repair. Cell Rep. 14, 1555–1566 (2016).
Crossref Google Scholar
152

Pinder, J., Salsman, J. & Dellaire, G. Nuclear domain ‘knock-in’ screen for the evaluation and identification of small molecule enhancers of CRISPR-based genome editing. Nucleic Acids Res. 43, 9379–9392 (2015).
Crossref Google Scholar
153

Niu, Y. et al. Generation of gene-modified cynomolgus monkey via Cas9/RNA-mediated gene targeting in one-cell embryos. Cell 156, 836–843 (2014).
Crossref Google Scholar
154

Steven, L., Staahl, B. T., Alla, R. K. & Doudna, J. A. Enhanced homology-directed human genome engineering by controlled timing of CRISPR/Cas9 delivery. eLife 3, e04766 (2014).
Crossref Google Scholar
155

Voytas, D. F. & Gao, C. Precision genome engineering and agriculture: opportunities and regulatory challenges. PLoS Biol. 12, e1001877 (2014).
Crossref Google Scholar
156

Lambert, L. J. et al. Increased trabecular bone and improved biomechanics in an osteocalcin-null rat model created by CRISPR/Cas9 technology. Dis. Model Mech. 9, 1169–1179 (2016).
Crossref Google Scholar
157

Matsukawa, A. & Yoshinaga, M. Sequential generation of cytokines during the initiative phase of inflammation, with reference to neutrophils. Inflamm. Res. 47, S137–S144 (1998).
Crossref Google Scholar
158

Cigan, A. D. et al. High seeding density of human chondrocytes in agarose produces tissue-engineered cartilage approaching native mechanical and biochemical properties. J. Biomech. 49, 1909–1917 (2016).
Crossref Google Scholar
159

Karlsen, T. A., Pernas, P. F., Staerk, J., Caglayan, S. & Brinchmann, J. E. Generation of IL1β-resistant chondrocytes using CRISPR-CAS genome editing. Osteoarthr. Cartil. 24, S325(2016).
Crossref Google Scholar
160

Eyquem, J. et al. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature 543, 113–117 (2017).
Crossref Google Scholar
161

Ran, F. A. et al. In vivo genome editing using Staphylococcus aureus Cas9. Nature 520, 186–191 (2015).
Crossref Google Scholar
162

Ho, B. X., Loh, S. J. H., Chan, W. K. & Soh, B. S. In vivo genome editing as a therapeutic approach. Int. J. Mol. Sci. 19, 3721 (2018).
Crossref Google Scholar
163

Chevalier, X., Eymard, F. & Richette, P. Biologic agents in osteoarthritis: hopes and disappointments. Nat. Rev. Rheumatol. 9, 400–410 (2013).
Crossref Google Scholar
164

Hellio Le Graverand-Gastineau, M. P. OA clinical trials: current targets and trials for OA. Choosing molecular targets: what have we learned and where we are headed? Osteoarthr. Cartil. 17, 1393–1401 (2009).
Crossref Google Scholar
165

Seidel, M. F., Wise, B. L. & Lane, N. E. Nerve growth factor: an update on the science and therapy. Osteoarthr. Cartil. 21, 1223–1228 (2013).
Crossref Google Scholar
166

Zhao, L. et al. Exploration of CRISPR/Cas9-based gene editing as therapy for osteoarthritis. Ann. Rheum. Dis. 78, 676–682 (2019).
Crossref Google Scholar
167

Enache, O. M. et al. Cas9 activates the p53 pathway and selects for p53-inactivating mutations. Nat. Genet. 52, 662–668 (2020).
Crossref Google Scholar
168

Kosicki, M., Tomberg, K. & Bradley, A. Repair of double-strand breaks induced by CRISPR-Cas9 leads to large deletions and complex rearrangements. Nat. Biotechnol. 36, 765–771 (2018).
Crossref Google Scholar
169

Xu, S. et al. CAS9 is a genome mutator by directly disrupting DNA-PK dependent DNA repair pathway. Protein Cell 11, 352–365 (2020).
Crossref Google Scholar
170

Abudayyeh, O. O. et al. RNA targeting with CRISPR-Cas13. Nature 550, 280–284 (2017).
Crossref Google Scholar
171

Xu, C. et al. Programmable RNA editing with compact CRISPR-Cas13 systems from uncultivated microbes. Nat. Methods 18, 499–506 (2021).
Crossref Google Scholar
172

Zeballos, C. M. & Gaj, T. Next-Generation CRISPR Technologies and Their Applications in Gene and Cell Therapy. Trends Biotechnol. 39, 692–705 (2021).
Crossref Google Scholar
173

He, B. et al. Modulation of metabolic functions through Cas13d-mediated gene knockdown in liver. Protein Cell 11, 518–524 (2020).
Crossref Google Scholar
174

Zhou, C. et al. CasRx-mediated RNA targeting prevents choroidal neovascularization in a mouse model of age-related macular degeneration. Natl. Sci. Rev. 7, 835–837 (2020).
Crossref Google Scholar
175

Lin, A. C. et al. Modulating hedgehog signaling can attenuate the severity of osteoarthritis. Nat. Med. 15, 1421–1425 (2009).
Crossref Google Scholar
176

Razzaque, M. S., Soegiarto, D. W., Chang, D., Long, F. & Lanske, B. Conditional deletion of Indian hedgehog from collagen type 2alpha1-expressing cells results in abnormal endochondral bone formation. J. Pathol. 207, 453–461 (2005).
Crossref Google Scholar
177

Wu, Z., Shou, L., Wang, J. & Xu, X. Identification of the key gene and pathways associated with osteoarthritis via single-cell RNA sequencing on synovial fibroblasts. Medicine 99, e21707 (2020).
Crossref Google Scholar
178

Ji, Q. et al. Single-cell RNA-seq analysis reveals the progression of human osteoarthritis. Ann. Rheum. Dis. 78, 100–110 (2019).
Crossref Google Scholar
179

Li, C. et al. Single cell sequencing revealed the underlying pathogenesis of the development of osteoarthritis. Gene 757, 144939 (2020).
Crossref Google Scholar
180

Maes, C. et al. Osteoblast precursors, but not mature osteoblasts, move into developing and fractured bones along with invading blood vessels. Dev. Cell 19, 329–344 (2010).
Crossref Google Scholar
181

Mizoguchi, T. et al. Osterix marks distinct waves of primitive and definitive stromal progenitors during bone marrow development. Dev. Cell 29, 340–349 (2014).
Crossref Google Scholar
182

Mizuhashi, K. et al. Resting zone of the growth plate houses a unique class of skeletal stem cells. Nature 563, 254–258 (2018).
Crossref Google Scholar
183

Ono, N. et al. Vasculature-associated cells expressing nestin in developing bones encompass early cells in the osteoblast and endothelial lineage. Dev. Cell 29, 330–339 (2014).
Crossref Google Scholar
184

Wang, T. et al. Specific deletion of beta-Catenin in Col2-expressing cells leads to defects in epiphyseal bone. Int. J. Biol. Sci. 13, 1540–1546 (2017).
Crossref Google Scholar
185

Kuang, D. Y. et al. Complete chloroplast genome sequence of Magnolia kwangsiensis (Magnoliaceae): implication for DNA barcoding and population genetics. Genome 54, 663–673 (2011).
Crossref Google Scholar
186

Hsu, C. M., de Palmas, S., Kuo, C. Y., Denis, V. & Chen, C. A. Identification of scleractinian coral recruits using fluorescent censusing and DNA barcoding techniques. PLoS One 9, e107366 (2014).
Crossref Google Scholar
187

McKenna, A. et al. Whole-organism lineage tracing by combinatorial and cumulative genome editing. Science 353, aaf7907 (2016).
Crossref Google Scholar
188

McKenna, A. & Gagnon, J. A. Recording development with single cell dynamic lineage tracing. Development 146 (2019).
Crossref Google Scholar
189

Wagner, D. E. & Klein, A. M. Lineage tracing meets single-cell omics: opportunities and challenges. Nat. Rev. Genet. 21, 410–427 (2020).
Crossref Google Scholar
190

Kebschull, J. M. & Zador, A. M. Cellular barcoding: lineage tracing, screening and beyond. Nat. Methods 15, 871–879 (2018).
Crossref Google Scholar
191

Galluzzi, L. et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 25, 486–541 (2018).
Crossref Google Scholar
192

Ameisen, J. C. On the origin, evolution, and nature of programmed cell death: a timeline of four billion years. Cell Death Differ. 9, 367–393 (2002).
Crossref Google Scholar
193

Elmore, S. Apoptosis: a review of programmed cell death. Toxicol. Pathol. 35, 495–516 (2007).
Crossref Google Scholar
194

Fuchs, Y. & Steller, H. Programmed cell death in animal development and disease. Cell 147, 742–758 (2011).
Crossref Google Scholar
195

Ouyang, L. et al. Programmed cell death pathways in cancer: a review of apoptosis, autophagy and programmed necrosis. Cell Prolif. 45, 487–498 (2012).
Crossref Google Scholar
196

Bedoui, S., Herold, M. J. & Strasser, A. Emerging connectivity of programmed cell death pathways and its physiological implications. Nat. Rev. Mol. Cell Biol. 21, 678–695 (2020).
Crossref Google Scholar
197

D’Souza, C. A. & Heitman, J. Dismantling the Cryptococcus coat. Trends Microbiol 9, 112–113 (2001).
Crossref Google Scholar
198

Broz, P. & Dixit, V. M. Inflammasomes: mechanism of assembly, regulation and signalling. Nat. Rev. Immunol. 16, 407–420 (2016).
Crossref Google Scholar
199

He, W. T. et al. Gasdermin D is an executor of pyroptosis and required for interleukin-1beta secretion. Cell Res. 25, 1285–1298 (2015).
Crossref Google Scholar
200

de Gassart, A. & Martinon, F. Pyroptosis: caspase-11 unlocks the gates of death. Immunity 43, 835–837 (2015).
Crossref Google Scholar
201

Kovacs, S. B. & Miao, E. A. Gasdermins: effectors of pyroptosis. Trends Cell Biol. 27, 673–684 (2017).
Crossref Google Scholar
202

Liu, X. et al. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature 535, 153–158 (2016).
Crossref Google Scholar
203

Wu, X., Ren, G., Zhou, R., Ge, J. & Chen, F. H. The role of Ca(2+) in acid-sensing ion channel 1a-mediated chondrocyte pyroptosis in rat adjuvant arthritis. Lab. Investig. 99, 499–513 (2019).
Crossref Google Scholar
204

Zhang, Y., Lin, Z., Chen, D. & He, Y. CY-09 attenuates the progression of osteoarthritis via inhibiting NLRP3 inflammasome-mediated pyroptosis. Biochem. Biophys. Res. Commun. 553, 119–125 (2021).
Crossref Google Scholar
205

Hu, J. et al. Loganin ameliorates cartilage degeneration and osteoarthritis development in an osteoarthritis mouse model through inhibition of NF-kappaB activity and pyroptosis in chondrocytes. J. Ethnopharmacol. 247, 112261 (2020).
Crossref Google Scholar
206

Zhang, L. et al. Increased HIF-1alpha in knee osteoarthritis aggravate synovial fibrosis via fibroblast-like synoviocyte pyroptosis. Oxid. Med. Cell Longev. 2019, 6326517 (2019).
Crossref Google Scholar
207

Xie, Y. et al. Ferroptosis: process and function. Cell Death Differ. 23, 369–379 (2016).
Crossref Google Scholar
208

Li, J. et al. Ferroptosis: past, present and future. Cell Death Dis. 11, 88 (2020).
Crossref Google Scholar
209

Dixon, S. J. et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149, 1060–1072 (2012).
Crossref Google Scholar
210

Imai, H., Matsuoka, M., Kumagai, T., Sakamoto, T. & Koumura, T. Lipid peroxidation-dependent cell death regulated by GPx4 and ferroptosis. Curr. Top. Microbiol. Immunol. 403, 143–170 (2017).
Crossref Google Scholar
211

Yang, W. S. & Stockwell, B. R. Ferroptosis: death by lipid peroxidation. Trends Cell Biol. 26, 165–176 (2016).
Crossref Google Scholar
212

Jiang, X., Stockwell, B. R. & Conrad, M. Ferroptosis: mechanisms, biology and role in disease. Nat. Rev. Mol. Cell Biol. 22, 266–282 (2021).
Crossref Google Scholar
213

Stockwell, B. R., Jiang, X. & Gu, W. Emerging mechanisms and disease relevance of ferroptosis. Trends Cell Biol. 30, 478–490 (2020).
Crossref Google Scholar
214

Mobasheri, A. et al. The role of metabolism in the pathogenesis of osteoarthritis. Nat. Rev. Rheumatol. 13, 302–311 (2017).
Crossref Google Scholar
215

Robinson, W. H. et al. Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis. Nat. Rev. Rheumatol. 12, 580–592 (2016).
Crossref Google Scholar
216

Yao, X. et al. Chondrocyte ferroptosis contribute to the progression of osteoarthritis. J. Orthop. Translat. 27, 33–43 (2021).
Crossref Google Scholar
217

Wang, S. et al. Mechanical overloading induces GPX4-regulated chondrocyte ferroptosis in osteoarthritis via Piezo1 channel facilitated calcium influx. J. Adv. Res. (2022).
Crossref Google Scholar
218

Wu, J. et al. Intercellular interaction dictates cancer cell ferroptosis via NF2-YAP signalling. Nature 572, 402–406 (2019).
Crossref Google Scholar
219

Yang, W. H. et al. The Hippo pathway effector TAZ regulates ferroptosis in renal cell carcinoma. Cell Rep. 28, 2501–2508 e2504 (2019).
Crossref Google Scholar
220

Yang, W. H. et al. The Hippo pathway effector YAP promotes ferroptosis via the E3 ligase SKP2. Mol. Cancer Res. 19, 1005–1014 (2021).
Crossref Google Scholar
221

Lee, H. et al. Energy-stress-mediated AMPK activation inhibits ferroptosis. Nat. Cell Biol. 22, 225–234 (2020).
Crossref Google Scholar
222

Li, C. et al. LKB1-AMPK axis negatively regulates ferroptosis by inhibiting fatty acid synthesis. Signal Transduct. Target Ther. 5, 187 (2020).
Crossref Google Scholar
223

Codogno, P., Mehrpour, M. & Proikas-Cezanne, T. Canonical and non-canonical autophagy: variations on a common theme of self-eating? Nat. Rev. Mol. Cell Biol. 13, 7–12 (2011).
Crossref Google Scholar
224

Nakamura, S. & Yoshimori, T. New insights into autophagosome-lysosome fusion. J. Cell Sci. 130, 1209–1216 (2017).
Crossref Google Scholar
225

Alers, S., Loffler, A. S., Wesselborg, S. & Stork, B. Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks. Mol. Cell. Biol. 32, 2–11 (2012).
Crossref Google Scholar
226

Moruno-Manchon, J. F., Perez-Jimenez, E. & Knecht, E. Glucose induces autophagy under starvation conditions by a p38 MAPK-dependent pathway. Biochem. J. 449, 497–506 (2013).
Crossref Google Scholar
227

Qin, L., Wang, Z., Tao, L. & Wang, Y. ER stress negatively regulates AKT/TSC/mTOR pathway to enhance autophagy. Autophagy 6, 239–247 (2010).
Crossref Google Scholar
228

Carames, B., Taniguchi, N., Otsuki, S., Blanco, F. J. & Lotz, M. Autophagy is a protective mechanism in normal cartilage, and its aging-related loss is linked with cell death and osteoarthritis. Arthritis Rheumatol. 62, 791–801 (2010).
Crossref Google Scholar
229

López de Figueroa, P., Lotz, M. K., Blanco, F. J. & Caramés, B. Autophagy activation and protection from mitochondrial dysfunction in human chondrocytes. Arthritis Rheumatol. 67, 966–976 (2015).
Crossref Google Scholar
230

Zhang, Y. et al. Cartilage-specific deletion of mTOR upregulates autophagy and protects mice from osteoarthritis. Ann. Rheum. Dis. 74, 1432–1440 (2015).
Crossref Google Scholar
231

Takayama, K. et al. Local intra-articular injection of rapamycin delays articular cartilage degeneration in a murine model of osteoarthritis. Arthritis Res. Ther. 16, 482 (2014).
Crossref Google Scholar
232

Zawieja, D. Lymphatic biology and the microcirculation: past, present and future. Microcirculation 12, 141–150 (2015).
Crossref Google Scholar
233

Wilting, J., Becker, J., Buttler, K. & Weich, H. A. Lymphatics and inflammation. Curr. Med. Chem. 16, 4581–4592 (2009).
Crossref Google Scholar
234

Fei, Z. et al. Akt/Protein kinase B is required for lymphatic network formation, remodeling, and valve development. Am. J. Pathol. 177, 2124–2133 (2010).
Crossref Google Scholar
235

van der Flier, A. et al. Endothelial alpha5 and alphav integrins cooperate in remodeling of the vasculature during development. Development 137, 2439–2449 (2010).
Crossref Google Scholar
236

Kenney, H. M. et al. Lineage tracing reveals evidence of a popliteal lymphatic muscle progenitor cell that is distinct from skeletal and vascular muscle progenitors. Sci. Rep. 10, 18088 (2020).
Crossref Google Scholar
237

Van Helden, D. F. Pacemaker potentials in lymphatic smooth muscle of the guinea-pig mesentery. J. Physiol. 471, 465–479 (1993).
Crossref Google Scholar
238

von der Weid, P. Y. & Zawieja, D. C. Lymphatic smooth muscle: the motor unit of lymph drainage. Int. J. Biochem. Cell Biol. 36, 1147–1153 (2004).
Crossref Google Scholar
239

Guo, R. et al. Inhibition of lymphangiogenesis and lymphatic drainage via vascular endothelial growth factor receptor 3 blockade increases the severity of inflammation in a mouse model of chronic inflammatory arthritis. Arthritis Rheumatol. 60, 2666–2676 (2010).
Crossref Google Scholar
240

Li, J. et al. Efficacy of B cell depletion therapy for murine joint arthritis flare is associated with increased lymphatic flow. Arthritis Rheumatol. 65, 130–138 (2013).
Crossref Google Scholar
241

Li, J., Quan, Z., Wood, R. W., Kuzin, I. & Schwarz, E. M. CD23/CD21B-cell translocation and ipsilateral lymph node collapse is associated with asymmetric arthritic flare in TNF-Tg mice. Arthritis Res. Ther. 13, R138 (2011).
Crossref Google Scholar
242

Liang, Q. et al. Lymphatic endothelial cells efferent to inflamed joints produce iNOS and inhibit lymphatic vessel contraction and drainage in TNF-induced arthritis in mice. Arthritis Res. Ther. 18, 62 (2016).
Crossref Google Scholar
243

Zhou, Q. et al. Vascular endothelial growth factor C attenuates joint damage in chronic inflammatory arthritis by accelerating local lymphatic drainage in mice. Arthritis Rheumatol. 63, 2318–2328 (2011).
Crossref Google Scholar
244

Zhou, Q., Wood, R., Schwarz, E. M., Wang, Y. J. & Xing, L. Near-infrared lymphatic imaging demonstrates the dynamics of lymph flow and lymphangiogenesis during the acute versus chronic phases of arthritis in mice. Arthritis Rheumatol. 62, 1881–1889 (2014).
Crossref Google Scholar
245

Shi, J. et al. Distribution and alteration of lymphatic vessels in knee joints of normal and osteoarthritic mice. Arthritis Rheumatol. 66, 657–666 (2014).
Crossref Google Scholar
246

Shi, J. X. et al. Use of a whole-slide imaging system to assess the presence and alteration of lymphatic vessels in joint sections of arthritic mice. Biotech. Histochem. 88, 428–439 (2013).
Crossref Google Scholar
247

Li, J. et al. Expanded CD23(+)/CD21(hi) B cells in inflamed lymph nodes are associated with the onset of inflammatory-erosive arthritis in TNF-transgenic mice and are targets of anti-CD20 therapy. J. Immunol. 184, 6142–6150 (2010).
Crossref Google Scholar
248

Bouta, E. M. et al. Targeting lymphatic function as a novel therapeutic intervention for rheumatoid arthritis. Nat. Rev. Rheumatol. 14, 94–106 (2018).
Crossref Google Scholar
249

Bell, R. D. et al. Altered lymphatic vessel anatomy and markedly diminished lymph clearance in affected hands of patients with active rheumatoid arthritis. Arthritis Rheumatol. 72, 1447–1455 (2020).
Crossref Google Scholar
250

Albuquerque, M. & de Lima, J. P. Articular lymphoscintigraphy in human knees using radiolabeled dextran. Lymphology 23, 215–218 (1990).
Google Scholar
251

Walsh, D. A. et al. Lymphatic vessels in osteoarthritic human knees. Osteoarthr. Cartil. 20, 405–412 (2012).
Crossref Google Scholar
252

Mesquita, S. D. et al. Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease. Nature 82, 185–191 (2018).
Crossref Google Scholar
253

Shaw, T., Nixon, J. S. & Bottomley, K. M. Metalloproteinase inhibitors: new opportunities for the treatment of rheumatoid arthritis and osteoarthritis. Expert Opin. Investig. Drugs 9, 1469–1478 (2000).
Crossref Google Scholar
254

Krzeski, P. et al. Development of musculoskeletal toxicity without clear benefit after administration of PG-116800, a matrix metalloproteinase inhibitor, to patients with knee osteoarthritis: a randomized, 12-month, double-blind, placebo-controlled study. Arthritis Res. Ther. 9, 1–11 (2007).
Crossref Google Scholar
255

Zhang, Y. et al. Activation of vascular endothelial growth factor receptor-3 in macrophages restrains TLR4-NF-κB signaling and protects against endotoxin shock. Immunity 40, 501–514 (2014).
Crossref Google Scholar
256

Shen, J. et al. Deletion of the type Ⅱ TGF-β receptor gene in articular chondrocytes leads to progressive OA-like phenotype in mice. Arthritis Rheum. 65, 3107–3119 (2013).
Crossref Google Scholar
257

Xia, C. et al. Activation of β-catenin in Col2-expressing chondrocytes leads to osteoarthritis-like defects in hip joint. J. Cell Physiol 234, 18535–18543 (2019).
Crossref Google Scholar
258
Lin, Xi. Impact of macrophages on the synovial lymphatic system in mice with posttraumatic osteoarthritis. PhD dissertation, University of Rochester (2020).
Bone Research
Volume 10,
December 2022
Article number: 60
DOI: 10.1038/s41413-022-00226-9
Cite this article:
Tong L, Yu H, Huang X, et al. Current understanding of osteoarthritis pathogenesis and relevant new approaches. Bone Research, 2022, 10: 60. https://doi.org/10.1038/s41413-022-00226-9

154

Views

7

Downloads

144

Crossref

124

Web of Science

137

Scopus

Altmetrics
Received: 04 April 2022
Revised: 27 May 2022
Accepted: 19 June 2022
Published: 20 September 2022
© The Author(s) 2022

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Return