Single‐cell RNA sequencing in osteoarthritis
Open accessAbstract
Osteoarthritis is a progressive and heterogeneous joint disease with complex pathogenesis. The various phenotypes associated with each patient suggest that better subgrouping of tissues associated with genotypes in different phases of osteoarthritis may provide new insights into the onset and progression of the disease. Recently, single‐cell RNA sequencing was used to describe osteoarthritis pathogenesis on a high‐resolution view surpassing traditional technologies. Herein, this review summarizes the microstructural changes in articular cartilage, meniscus, synovium and subchondral bone that are mainly due to crosstalk amongst chondrocytes, osteoblasts, fibroblasts and endothelial cells during osteoarthritis progression. Next, we focus on the promising targets discovered by single‐cell RNA sequencing and its potential applications in target drugs and tissue engineering. Additionally, the limited amount of research on the evaluation of bone‐related biomaterials is reviewed. Based on the pre‐clinical findings, we elaborate on the potential clinical values of single‐cell RNA sequencing for the therapeutic strategies of osteoarthritis. Finally, a perspective on the future development of patient‐centred medicine for osteoarthritis therapy combining other single‐cell multi‐omics technologies is discussed. This review will provide new insights into osteoarthritis pathogenesis on a cellular level and the field of applications of single‐cell RNA sequencing in personalized therapeutics for osteoarthritis in the future.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Single-cell RNA sequencing, ATAC-seq, proteomics, and spatial transcriptomics provide unprecedented resolution of cellular heterogeneity, revealing distinct cell subpopulations and molecular signatures in joint tissues that drive pathogenesis.
“Single-cell RNA sequencing, ATAC-seq, proteomics, and spatial transcriptomics provide an unprecedented resolution of cellular heterogeneity, revealing distinct cell subpopulations and molecular signatures in joint tissues that drive pathogenesis”
From Biomarker-Guided Imaging and AI-Augmented Diagnosis of Degenerative Joint Disease (2025) · cites this paper as [160]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredSingle-cell technologies offer potential cellular biomarkers for precise disease classification and targeted therapies.
“offering potential cellular biomarkers for precise disease classification and targeted therapies [159,160].”
From Biomarker-Guided Imaging and AI-Augmented Diagnosis of Degenerative Joint Disease (2025) · cites this paper as [160]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Smart-seq2 for sensitive full-length transcriptome profiling in single cells
Picelli, S., Björklund, Å. K., Faridani, O. R., Sagasser, S., Winberg, G., & Sandberg, R. (2013) · Nature Methods · doi:10.1038/nmeth.2639 · Cited by 2,358 · see citing works
Distinct fibroblast subsets drive inflammation and damage in arthritis
Croft, A. P., Campos, J., Jansen, K., Turner, J. D., Marshall, J., Attar, M., Savary, L., Wehmeyer, C., Naylor, A. J., Kemble, S., et al. (2019) · Nature · doi:10.1038/s41586-019-1263-7 · Cited by 976 · see citing works
Denisenko, E., Guo, B. B., Jones, M., Hou, R., de Kock, L., Lassmann, T., Poppe, D., Clément, O., Simmons, R. K., Lister, R., et al. (2020) · Genome Biology · doi:10.1186/s13059-020-02048-6 · Cited by 686 · see citing works
Subchondral bone microenvironment in osteoarthritis and pain
Hu, Y., Chen, X., Wang, S., Jing, Y., & Su, J. (2021) · Bone Research · doi:10.1038/s41413-021-00147-z · Cited by 577 · see citing works
Self-citationTherapeutic options for targeting inflammatory osteoarthritis pain
Conaghan, P. G., Cook, A. D., Hamilton, J. A., & Tak, P. P. (2019) · Nature Reviews Rheumatology · doi:10.1038/s41584-019-0221-y · Cited by 405 · see citing works
Massively multiplex chemical transcriptomics at single-cell resolution
Srivatsan, S. R., McFaline-Figueroa, J. L., Ramani, V., Saunders, L., Cao, J., Packer, J., Pliner, H. A., Jackson, D. L., Daza, R. M., Christiansen, L., et al. (2020) · Science · doi:10.1126/science.aax6234 · Cited by 401 · see citing works
Cohen, Y. C., Zada, M., Wang, S.-Y., Bornstein, C., David, E., Moshe, A., Li, B., Shlomi-Loubaton, S., Gatt, M. E., Gur, C., et al. (2021) · Nature Medicine · doi:10.1038/s41591-021-01232-w · Cited by 235 · see citing works
Self-citationTargeting actin-bundling protein L-plastin as an anabolic therapy for bone loss
Li, X., Wang, L., Huang, B., Gu, Y., Luo, Y., Zhi, X., Hu, Y., Zhang, H., Gu, Z., Cui, J., et al. (2020) · Science Advances · doi:10.1126/sciadv.abb7135 · Cited by 90 · see citing works
Self-citationJung, S., Singh, K., & del Sol, A. (2021) · Briefings in Bioinformatics · doi:10.1093/bib/bbaa283 · Cited by 9 · see citing works
Flagged first, then by citations
Research works printed but not linked: 171
- [1]Katz JN, Arant KR, Loeser RF. Diagnosis and treatment of hip and knee osteoarthritis: a review. JAMA. 2021; 325: 568‐ 578. 33560326 PMC8225295
- [2]Bijlsma JWJ, Berenbaum F, Lafeber FPJG. Osteoarthritis: an update with relevance for clinical practice. Lancet. 2011; 377: 2115‐ 2126. 21684382
- [3]Hunter DJ, Bierma‐Zeinstra S. Osteoarthritis. Lancet. 2019; 393: 1745‐ 1759. 31034380
- [4]Yuan C, Pan Z, Zhao K, et al. Classification of four distinct osteoarthritis subtypes with a knee joint tissue transcriptome atlas. Bone Res. 2020; 8: 38. 33298863 PMC7658991
- [5]Chen D, Shen J, Zhao W, et al. Osteoarthritis: toward a comprehensive understanding of pathological mechanism. Bone Res. 2017; 5: 16044. 28149655 PMC5240031
- [6]Castaneda S, Roman‐Blas JA, Largo R, Herrero‐Beaumont G. Osteoarthritis: a progressive disease with changing phenotypes. Rheumatology (Oxford). 2014; 53: 1‐ 3. 23878311
- [7]Shalek AK, Satija R, Shuga J, et al. Single‐cell RNA‐seq reveals dynamic paracrine control of cellular variation. Nature. 2014; 510: 363‐ 369. 24919153 PMC4193940
- [8]Haque A, Engel J, Teichmann SA, Lonnberg T. A practical guide to single‐cell RNA‐sequencing for biomedical research and clinical applications. Genome Med. 2017; 9: 75. 28821273 PMC5561556
- [9]Tang F, Barbacioru C, Wang Y, et al. mRNA‐Seq whole‐transcriptome analysis of a single cell. Nat Methods. 2009; 6: 377‐ 382. 19349980
- [10]Peng J, Sun BF, Chen CY, et al. Single‐cell RNA‐seq highlights intra‐tumoral heterogeneity and malignant progression in pancreatic ductal adenocarcinoma. Cell Res. 2019; 29: 725‐ 738. 31273297 PMC6796938
- [11]Jia Q, Chu H, Jin Z, Long H, Zhu B. High‐throughput single‐сell sequencing in cancer research. Signal Transduct Target Ther. 2022; 7: 145. PMC9065032 35504878
- [12]Hwang B, Lee JH, Bang D. Single‐cell RNA sequencing technologies and bioinformatics pipelines. Exp Mol Med. 2018; 50: 1‐ 14. PMC6082860 30089861
- [13]Jindal A, Gupta P, Jayadeva, Sengupta D. Discovery of rare cells from voluminous single cell expression data. Nat Commun. 2018; 9(1): 4719. 30413715 PMC6226447
- [15]Deng Q, Ramsköld D, Reinius B, Sandberg R. Single‐cell RNA‐seq reveals dynamic, random monoallelic gene expression in mammalian cells. Science. 2014; 343: 193‐ 196. 24408435
- [16]Greenblatt MB, Ono N, Ayturk UM, Debnath S, Lalani S. The Unmixing problem: a guide to applying single‐cell RNA sequencing to bone. J Bone Miner Res. 2019; 34: 1207‐ 1219. 31336008 PMC6658136
- [17]Fang C, Guo JW, Wang YJ, et al. Diterbutyl phthalate attenuates osteoarthritis in ACLT mice via suppressing ERK/c‐fos/NFATc1 pathway, and subsequently inhibiting subchondral osteoclast fusion. Acta Pharmacol Sin. 2022; 43: 1299‐ 1310. 34381182 PMC9061820
- [18]Mei Z, Dong X, Qian Y, et al. Association between the metabolome and bone mineral density in a Chinese population. EBioMedicine. 2020; 62: 103111. 33186808 PMC7670189
- [19]Glyn‐Jones S, Palmer AJR, Agricola R, et al. Osteoarthritis. Lancet. 2015; 386: 376‐ 387. 25748615
- [20]Papalexi E, Satija R. Single‐cell RNA sequencing to explore immune cell heterogeneity. Nat Rev Immunol. 2018; 18: 35‐ 45. 28787399
- [21]Nguyen A, Khoo WH, Moran I, Croucher PI, Phan TG. Single cell RNA sequencing of rare immune cell populations. Front Immunol. 2018; 9: 1553. 30022984 PMC6039576
- [22]Mereu E, Lafzi A, Moutinho C, et al. Benchmarking single‐cell RNA‐sequencing protocols for cell atlas projects. Nat Biotechnol. 2020; 38: 747‐ 755. 32518403
- [23]Paik DT, Cho S, Tian L, Chang HY, Wu JC. Single‐cell RNA sequencing in cardiovascular development, disease and medicine. Nat Rev Cardiol. 2020; 17: 457‐ 473. 32231331 PMC7528042
- [25]O'Flanagan CH, Campbell KR, Zhang AW, et al. Dissociation of solid tumor tissues with cold active protease for single‐cell RNA‐seq minimizes conserved collagenase‐associated stress responses. Genome Biol. 2019; 20: 210. 31623682 PMC6796327
- [26]Zhao XM, Cui LS, Hao HS, et al. Transcriptome analyses of inner cell mass and trophectoderm cells isolated by magnetic‐activated cell sorting from bovine blastocysts using single cell RNA‐seq. reproduction in domestic animals =. Zuchthygiene. 2016; 51: 726‐ 735. 27440443
- [27]Kulkarni A, Anderson AG, Merullo DP, Konopka G. Beyond bulk: a review of single cell transcriptomics methodologies and applications. Curr Opin Biotechnol. 2019; 58: 129‐ 136. 30978643 PMC6710112
- [28]Citri A, Pang ZP, Südhof TC, Wernig M, Malenka RC. Comprehensive qPCR profiling of gene expression in single neuronal cells. Nat Protoc. 2011; 7: 118‐ 127. 22193304 PMC4377330
- [29]Nichterwitz S, Chen G, Aguila Benitez J, et al. Laser capture microscopy coupled with smart‐seq2 for precise spatial transcriptomic profiling. Nat Commun. 2016; 7: 12139. 27387371 PMC4941116
- [30]Bendall SC, Nolan GP, Roederer M, Chattopadhyay PK. A deep profiler's guide to cytometry. Trends Immunol. 2012; 33: 323‐ 332. 22476049 PMC3383392
- [31]Ayturk U. RNA‐seq in skeletal biology. Curr Osteoporos Rep. 2019; 17: 178‐ 185. 31093870
- [32]Debnath S, Yallowitz AR, McCormick J, et al. Discovery of a periosteal stem cell mediating intramembranous bone formation. Nature. 2018; 562: 133‐ 139. 30250253 PMC6193396
- [33]Takahashi A, Nagata M, Gupta A, et al. Autocrine regulation of mesenchymal progenitor cell fates orchestrates tooth eruption. Proc Natl Acad Sci U S A. 2019; 116: 575‐ 580. 30509999 PMC6329940
- [34]Chen TN, Gupta A, Zalavadia MD, Streets A. μCB‐seq: microfluidic cell barcoding and sequencing for high‐resolution imaging and sequencing of single cells. Lab Chip. 2020; 20: 3899‐ 3913. 32931539 PMC8256654
- [35]Svensson V. Droplet scRNA‐seq is not zero‐inflated. Nat Biotechnol. 2020; 38: 147‐ 150. 31937974
- [36]Stott SL, Lee RJ, Nagrath S, et al. Isolation and characterization of circulating tumor cells from patients with localized and metastatic prostate cancer. Sci Transl Med. 2010; 2: 25ra23. PMC3141292 20424012
- [37]Hashimshony T, Senderovich N, Avital G, et al. CEL‐Seq2: sensitive highly‐multiplexed single‐cell RNA‐Seq. Genome Biol. 2016; 17: 77. 27121950 PMC4848782
- [38]Mary P, Dauphinot L, Bois N, Potier MC, Studer V, Tabeling P. Analysis of gene expression at the single‐cell level using microdroplet‐based microfluidic technology. Biomicrofluidics. 2011; 5: 24109. 21716808 PMC3124518
- [39]Machado L, Esteves de Lima J, Fabre O, et al. In situ fixation redefines quiescence and early activation of skeletal muscle stem cells. Cell Rep. 2017; 21: 1982‐ 1993. 29141227
- [40]Buenrostro JD, Wu B, Litzenburger UM, et al. Single‐cell chromatin accessibility reveals principles of regulatory variation. Nature. 2015; 523: 486‐ 490. 26083756 PMC4685948
- [41]Kim TH, Zhou X, Chen M. Demystifying “drop‐outs” in single‐cell UMI data. Genome Biol. 2020; 21: 196. 32762710 PMC7412673
- [43]Mamanova L, Miao Z, Jinat A, Ellis P, Shirley L, Teichmann SA. High‐throughput full‐length single‐cell RNA‐seq automation. Nat Protoc. 2021; 16: 2886‐ 2915. 33990801
- [44]Wang X, He Y, Zhang Q, Ren X, Zhang Z. Direct comparative analyses of 10X genomics chromium and smart‐seq2. Genomics Proteomics Bioinformatics. 2021; 19: 253‐ 266. 33662621 PMC8602399
- [45]Butler A, Hoffman P, Smibert P, Papalexi E, Satija R. Integrating single‐cell transcriptomic data across different conditions, technologies, and species. Nat Biotechnol. 2018; 36: 411‐ 420. 29608179 PMC6700744
- [46]Huang ZY, Luo ZY, Cai YR, et al. Single cell transcriptomics in human osteoarthritis synovium and in silico deconvoluted bulk RNA sequencing. Osteoarthr Cartil. 2022; 30: 475‐ 480. PMC10097426 34971754
- [47]Barile M, Imaz‐Rosshandler I, Inzani I, et al. Coordinated changes in gene expression kinetics underlie both mouse and human erythroid maturation. Genome Biol. 2021; 22: 197. 34225769 PMC8258993
- [48]Kolodziejczyk AA, Kim JK, Svensson V, Marioni JC, Teichmann SA. The technology and biology of single‐cell RNA sequencing. Mol Cell. 2015; 58: 610‐ 620. 26000846
- [49]Yajun W, Jin C, Zhengrong G, et al. Betaine attenuates osteoarthritis by inhibiting Osteoclastogenesis and angiogenesis in subchondral bone. Front Pharmacol. 2021; 12: 723988. 34658862 PMC8511433
- [50]Chang SH, Mori D, Kobayashi H, et al. Excessive mechanical loading promotes osteoarthritis through the gremlin‐1‐NF‐κB pathway. Nat Commun. 2019; 10: 1442. 30926814 PMC6441020
- [51]Berenbaum F. Deep phenotyping of osteoarthritis: a step forward. Ann Rheum Dis. 2019; 78: 3‐ 5. 30154088
- [52]Prein C, Warmbold N, Farkas Z, Schieker M, Aszodi A, Clausen‐Schaumann H. Structural and mechanical properties of the proliferative zone of the developing murine growth plate cartilage assessed by atomic force microscopy. Matrix Biol. 2016; 50: 1‐ 15. 26454027
- [53]Ji Q, Zheng Y, Zhang G, et al. Single‐cell RNA‐seq analysis reveals the progression of human osteoarthritis. Ann Rheum Dis. 2019; 78: 100‐ 110. 30026257 PMC6317448
- [54]Chen Y, Yu Y, Wen Y, et al. A high‐resolution route map reveals distinct stages of chondrocyte dedifferentiation for cartilage regeneration. Bone Res. 2022; 10: 38. 35477573 PMC9046296
- [55]Jeon J, Oh H, Lee G, et al. Cytokine‐like 1 knock‐out mice (Cytl1−/−) show normal cartilage and bone development but exhibit augmented osteoarthritic cartilage destruction. J Biol Chem. 2011; 286: 27206‐ 27213. 21652695 PMC3149314
- [56]Baboolal TG, Mastbergen SC, Jones E, Calder SJ, Lafeber FP, McGonagle D. Synovial fluid hyaluronan mediates MSC attachment to cartilage, a potential novel mechanism contributing to cartilage repair in osteoarthritis using knee joint distraction. Ann Rheum Dis. 2016; 75: 908‐ 915. 25948596 PMC4853581
- [57]Sebastian A, Murugesh DK, Mendez ME, et al. Global gene expression analysis identifies age‐related differences in knee joint transcriptome during the development of post‐traumatic osteoarthritis in mice. Int J Mol Sci. 2020; 21(1):364. PMC6982134 31935848
- [58]Wang X, Ning Y, Zhang P, et al. Comparison of the major cell populations among osteoarthritis, Kashin‐Beck disease and healthy chondrocytes by single‐cell RNA‐seq analysis. Cell Death Dis. 2021; 12: 551. 34045450 PMC8160352
- [59]Szychlinska MA, Trovato FM, Di Rosa M, et al. Co‐expression and Co‐localization of cartilage glycoproteins CHI3L1 and Lubricin in osteoarthritic cartilage: morphological, Immunohistochemical and gene expression profiles. Int J Mol Sci. 2016; 17: 359. 26978347 PMC4813220
- [60]Li H, Yang HH, Sun ZG, Tang HB, Min JK. Whole‐transcriptome sequencing of knee joint cartilage from osteoarthritis patients. Bone Joint Res. 2019; 8: 290‐ 303. 31463037 PMC6691371
- [61]Park S, Arai Y, Bello A, et al. SPRY4 acts as an indicator of osteoarthritis severity and regulates chondrocyte hypertrophy and ECM protease expression. NPJ Regenerative Med. 2021; 6: 56. PMC8448831 34535669
- [62]van der Kraan PM, van den Berg WB. Chondrocyte hypertrophy and osteoarthritis: role in initiation and progression of cartilage degeneration? Osteoarthr Cartil. 2012; 20: 223‐ 232. 22178514
- [63]Bertrand J, Kräft T, Gronau T, et al. BCP crystals promote chondrocyte hypertrophic differentiation in OA cartilage by sequestering Wnt3a. Ann Rheum Dis. 2020; 79: 975‐ 984. 32371389
- [64]He CP, Jiang XC, Chen C, et al. The function of lncRNAs in the pathogenesis of osteoarthritis. Bone Joint Res. 2021; 10: 122‐ 133. 33560158 PMC7937410
- [65]Li X, Liao Z, Deng Z, Chen N, Zhao L. lncRNACombining bulk and single‐cell RNA‐sequencing data to reveal gene expression pattern of chondrocytes in the osteoarthritic knee. Bioengineered. 2021; 12: 997‐ 1007. 33749514 PMC8806218
- [66]Cao L, Weng W, Chen X, et al. Promotion of in vivo degradability, vascularization and osteogenesis of calcium sulfate‐based bone cements containing nanoporous lithium doping magnesium silicate. Int J Nanomedicine. 2017; 12: 1341‐ 1352. 28260883 PMC5325137
- [67]Rim YA, Nam Y, Ju JH. The role of chondrocyte hypertrophy and senescence in osteoarthritis initiation and progression. Int J Mol Sci. 2020; 21(7):2358. PMC7177949 32235300
- [68]Peng Z, Sun H, Bunpetch V, et al. The regulation of cartilage extracellular matrix homeostasis in joint cartilage degeneration and regeneration. Biomaterials. 2021; 268: 120555. 33285440
- [69]Chan DD, Li J, Luo W, Predescu DN, Cole BJ, Plaas A. Pirfenidone reduces subchondral bone loss and fibrosis after murine knee cartilage injury. J Orthop Res. 2018; 36: 365‐ 376. 28646530 PMC5742076
- [70]Chou CH, Jain V, Gibson J, et al. Synovial cell cross‐talk with cartilage plays a major role in the pathogenesis of osteoarthritis. Sci Rep. 2020; 10: 10868. 32616761 PMC7331607
- [71]Tsolis KC, Bei ES, Papathanasiou I, et al. Comparative proteomic analysis of hypertrophic chondrocytes in osteoarthritis. Clin Proteomics. 2015; 12: 12. 25945082 PMC4415313
- [72]Li C, Luo J, Xu X, et al. Single cell sequencing revealed the underlying pathogenesis of the development of osteoarthritis. Gene. 2020; 757: 144939. 32640306
- [73]Nardone G, Oliver‐De La Cruz J, Vrbsky J, et al. YAP regulates cell mechanics by controlling focal adhesion assembly. Nat Commun. 2017; 8: 15321. 28504269 PMC5440673
- [74]Prasadam I, Farnaghi S, Feng JQ, et al. Impact of extracellular matrix derived from osteoarthritis subchondral bone osteoblasts on osteocytes: role of integrinβ1 and focal adhesion kinase signaling cues. Arthritis Res Ther. 2013; 15: R150. 24289792 PMC3978998
- [75]Kennedy D, Mnich K, Oommen D, et al. HSPB1 facilitates ERK‐mediated phosphorylation and degradation of BIM to attenuate endoplasmic reticulum stress‐induced apoptosis. Cell Death Dis. 2017; 8: e3026. 29048431 PMC5596589
- [76]Lv Z, Han J, Li J, et al. Single cell RNA‐seq analysis identifies ferroptotic chondrocyte cluster and reveals TRPV1 as an anti‐ferroptotic target in osteoarthritis. EBioMedicine. 2022; 84: 104258. 36137413 PMC9494174
- [77]Poulsen RC, Hearn JI, Dalbeth N. The circadian clock: a central mediator of cartilage maintenance and osteoarthritis development? Rheumatology (Oxford). 2021; 60: 3048‐ 3057. 33630038
- [78]Lee KI, Choi S, Matsuzaki T, et al. FOXO1 and FOXO3 transcription factors have unique functions in meniscus development and homeostasis during aging and osteoarthritis. Proc Natl Acad Sci U S A. 2020; 117: 3135‐ 3143. 31980519 PMC7022148
- [79]Wang C, Shen J, Ying J, Xiao D, O'Keefe RJ. FoxO1 is a crucial mediator of TGF‐β/TAK1 signaling and protects against osteoarthritis by maintaining articular cartilage homeostasis. Proc Natl Acad Sci U S A. 2020; 117: 30488‐ 30497. 33199631 PMC7720227
- [80]Jiang Y, Tuan RS. Origin and function of cartilage stem/progenitor cells in osteoarthritis. Nat Rev Rheumatol. 2015; 11: 206‐ 212. 25536487 PMC5413931
- [81]Wang F, Guo J, Wang S, et al. B‐cell lymphoma‐3 controls mesenchymal stem cell commitment and senescence during skeletal aging. Clin Transl Med. 2022; 12: e955. 35804493 PMC9270574
- [82]Scanzello CR, Goldring SR. The role of synovitis in osteoarthritis pathogenesis. Bone. 2012; 51: 249‐ 257. 22387238 PMC3372675
- [83]Wang D, Chai XQ, Hu SS, Pan F. Joint synovial macrophages as a potential target for intra‐articular treatment of osteoarthritis‐related pain. Osteoarthr Cartil. 2022; 30: 406‐ 415. 34861384
- [84]Zhang F, Wei K, Slowikowski K, et al. Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single‐cell transcriptomics and mass cytometry. Nat Immunol. 2019; 20: 928‐ 942. 31061532 PMC6602051
- [85]Nanus DE, Badoume A, Wijesinghe SN, et al. Synovial tissue from sites of joint pain in knee osteoarthritis patients exhibits a differential phenotype with distinct fibroblast subsets. EBioMedicine. 2021; 72: 103618. 34628351 PMC8511845
- [86]Pethő Z, Tanner MR, Tajhya RB, et al. Different expression of β subunits of the KCa1.1 channel by invasive and non‐invasive human fibroblast‐like synoviocytes. Arthritis Res Ther. 2016; 18: 103. 27165430 PMC4863321
- [87]Thomson CA, van de Pavert SA, Stakenborg M, et al. Expression of the atypical chemokine receptor ACKR4 identifies a novel population of intestinal submucosal fibroblasts that preferentially expresses endothelial cell regulators. J Immunol. 2018; 201: 215‐ 229. 29760193 PMC6013047
- [88]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 (Baltimore). 2020; 99: e21707. 32872047 PMC7437759
- [89]Aladal M, You W, Huang R, et al. Insights into the implementation of fibronectin 1 in the cartilage tissue engineering. Biomed Pharmacother. 2022; 148: 112782. 35248846
- [90]Schröder A, Nazet U, Muschter D, Grässel S, Proff P, Kirschneck C. Impact of mechanical load on the expression profile of synovial fibroblasts from patients with and without osteoarthritis. Int J Mol Sci. 2019; 20(3):585. PMC6387339 30704030
- [91]Cai S, Ming B, Ye C, et al. Similar transition processes in synovial fibroblasts from rheumatoid arthritis and osteoarthritis: a single‐cell study. J Immunol Res. 2019; 2019: 4080735. 31428656 PMC6681591
- [92]Bondeson J, Wainwright SD, Lauder S, Amos N, Hughes CE. The role of synovial macrophages and macrophage‐produced cytokines in driving aggrecanases, matrix metalloproteinases, and other destructive and inflammatory responses in osteoarthritis. Arthritis Res Ther. 2006; 8: R187. 17177994 PMC1794533
- [93]Culemann S, Grüneboom A, Nicolás‐Ávila J, et al. Locally renewing resident synovial macrophages provide a protective barrier for the joint. Nature. 2019; 572: 670‐ 675. 31391580 PMC6805223
- [94]Zhou J, Zhao Z, He C, et al. Single‐cell transcriptome analysis profile of meniscal tissue macrophages in human osteoarthritis. J Immunol Res. 2020; 2020: 8127281. 32775469 PMC7407017
- [95]Wijesinghe SN, Badoume A, Nanus DE, et al. Obesity defined molecular endotypes in the synovium of patients with osteoarthritis provides a rationale for therapeutic targeting of fibroblast subsets. Clin Transl Med. 2023; 13: e1232. 37006170 PMC10068310
- [97]Englund M, Roemer FW, Hayashi D, Crema MD, Guermazi A. Meniscus pathology, osteoarthritis and the treatment controversy. Nat Rev Rheumatol. 2012; 8: 412‐ 419. 22614907
- [98]Rai MF, Brophy RH, Rosen V. Molecular biology of meniscus pathology: lessons learned from translational studies and mouse models. J Orthop Res. 2020; 38: 1895‐ 1904. 32068295 PMC7802285
- [99]Brophy RH, Zhang B, Cai L, Wright RW, Sandell LJ, Rai MF. Transcriptome comparison of meniscus from patients with and without osteoarthritis. Osteoarthr Cartil. 2018; 26: 422‐ 432. PMC6007850 29258882
- [100]Sun H, Wen X, Li H, et al. Single‐cell RNA‐seq analysis identifies meniscus progenitors and reveals the progression of meniscus degeneration. Ann Rheum Dis. 2020; 79: 408‐ 417. 31871141 PMC7034356
- [101]Xue X, Hu Y, Wang S, Chen X, Jiang Y, Su J. Fabrication of physical and chemical crosslinked hydrogels for bone tissue engineering. Bioact Mater. 2022; 12: 327‐ 339. 35128180 PMC8784310
- [102]Sun H, Zhang W, Liu F, et al. Single‐cell RNA sequencing reveals the cell types heterogenicity of human discoid lateral meniscus cells. J Cell Physiol. 2022; 237: 2469‐ 2477. 35220586
- [103]Chang JC, Christiansen BA, Murugesh DK, et al. SOST/Sclerostin improves posttraumatic osteoarthritis and inhibits MMP2/3 expression after injury. J Bone Miner Res. 2018; 33: 1105‐ 1113. 29377313 PMC6033030
- [104]Zhang Y, Li S, Jin P, et al. Dual functions of microRNA‐17 in maintaining cartilage homeostasis and protection against osteoarthritis. Nat Commun. 2022; 13: 2447. 35508470 PMC9068604
- [105]Mapp PI, Walsh DA. Mechanisms and targets of angiogenesis and nerve growth in osteoarthritis. Nat Rev Rheumatol. 2012; 8: 390‐ 398. 22641138
- [106]Lu D, Wei J, Chen J, et al. Apelin alleviates meniscus endothelial cell apoptosis in osteoarthritis. Dis Markers. 2022; 2022: 3556372. 35069930 PMC8777459
- [107]Hu W, Chen Y, Dou C, Dong S. Microenvironment in subchondral bone: predominant regulator for the treatment of osteoarthritis. Ann Rheum Dis. 2021; 80: 413‐ 422. 33158879 PMC7958096
- [109]Wang L, Zhang H, Wang S, Chen X, Su J. Bone marrow adipocytes: a critical player in the bone marrow microenvironment. Front Cell Dev Biol. 2021; 9: 770705. 34912805 PMC8667222
- [110]Li J, Yin Z, Huang B, Xu K, Su J. Stat3 signaling pathway: a future therapeutic target for bone‐related diseases. Front Pharmacol. 2022; 13: 897539. 35548357 PMC9081430
- [111]Tuerlings M, van Hoolwerff M, Houtman E, et al. RNA sequencing reveals interacting key determinants of osteoarthritis acting in subchondral bone and articular cartilage: identification of IL11 and CHADL as attractive treatment targets. Arthritis Rheumatol. 2021; 73: 789‐ 799. 33258547 PMC8252798
- [112]Kuliwaba JS, Findlay DM, Atkins GJ, Forwood MR, Fazzalari NL. Enhanced expression of osteocalcin mRNA in human osteoarthritic trabecular bone of the proximal femur is associated with decreased expression of interleukin‐6 and interleukin‐11 mRNA. J Bone Miner Res. 2000; 15: 332‐ 341. 10703936
- [113]Hu Y, Cui J, Liu H, et al. Single‐cell RNA‐sequencing analysis reveals the molecular mechanism of subchondral bone cell heterogeneity in the development of osteoarthritis. RMD Open. 2022; 8: e002314.
- [114]Song H, Li X, Zhao Z, et al. Reversal of osteoporotic activity by endothelial cell‐secreted bone targeting and biocompatible exosomes. Nano Lett. 2019; 19: 3040‐ 3048. 30968694
- [115]Peng Y, Wu S, Li Y, Crane JL. Type H blood vessels in bone modeling and remodeling. Theranostics. 2020; 10: 426‐ 436. 31903130 PMC6929606
- [116]Hu Y, Li X, Zhi X, et al. RANKL from bone marrow adipose lineage cells promotes osteoclast formation and bone loss. EMBO Rep. 2021; 22: e52481. 34121311 PMC8406405
- [117]Chen X, Zhi X, Wang J, Su J. RANKL signaling in bone marrow mesenchymal stem cells negatively regulates osteoblastic bone formation. Bone Res. 2018; 6: 34. 30510839 PMC6255918
- [118]Zhen G, Cao X. Targeting TGFβ signaling in subchondral bone and articular cartilage homeostasis. Trends Pharmacol Sci. 2014; 35: 227‐ 236. 24745631 PMC4058854
- [119]Sun P, He L, Jia K, et al. Regulation of body length and bone mass by Gpr126/Adgrg6. Sci Adv. 2020; 6: eaaz0368. 32219165 PMC7083604
- [120]Van Spil WE, Kubassova O, Boesen M, Bay‐Jensen AC, Mobasheri A. Osteoarthritis phenotypes and novel therapeutic targets. Biochem Pharmacol. 2019; 165: 41‐ 48. 30831073
- [121]Mao L, Wu W, Wang M, et al. Targeted treatment for osteoarthritis: drugs and delivery system. Drug Deliv. 2021; 28: 1861‐ 1876. 34515606 PMC8439249
- [122]Zhou D, Zhang H, Xue X, et al. Safety evaluation of natural drugs in chronic skeletal disorders: a literature review of clinical trials in the past 20 years. Front Pharmacol. 2021; 12: 801287. 35095508 PMC8793129
- [123]Robinson WH, Lepus CM, Wang Q, et al. Low‐grade inflammation as a key mediator of the pathogenesis of osteoarthritis. Nat Rev Rheumatol. 2016; 12: 580‐ 592. 27539668 PMC5500215
- [124]Latourte A, Kloppenburg M, Richette P. Emerging pharmaceutical therapies for osteoarthritis. Nat Rev Rheumatol. 2020; 16: 673‐ 688. 33122845
- [125]Chen Y, Wu X, Li J, Jiang Y, Xu K, Su J. Bone‐targeted nanoparticle drug delivery system: An emerging strategy for bone‐related disease. Front Pharmacol. 2022; 13: 909408. 35712701 PMC9195145
- [126]Hu Y, Li X, Zhang Q, et al. Exosome‐guided bone targeted delivery of Antagomir‐188 as an anabolic therapy for bone loss. Bioact Mater. 2021; 6: 2905‐ 2913. 33718671 PMC7917458
- [127]Ren X, Liu H, Wu X, Weng W, Wang X, Su J. Reactive oxygen species (ROS)‐responsive biomaterials for the treatment of bone‐related diseases. Front Bioeng Biotechnol. 2021; 9: 820468. 35087811 PMC8787194
- [128]Fu W, Hettinghouse A, Chen Y, et al. 14‐3‐3 epsilon is an intracellular component of TNFR2 receptor complex and its activation protects against osteoarthritis. Ann Rheum Dis. 2021; 80: 1615‐ 1627. 34226187 PMC8595573
- [129]Zhang Y, Guo W, Wang M, et al. Co‐culture systems‐based strategies for articular cartilage tissue engineering. J Cell Physiol. 2018; 233: 1940‐ 1951. 28548713
- [130]Harrell CR, Markovic BS, Fellabaum C, Arsenijevic A, Volarevic V. Mesenchymal stem cell‐based therapy of osteoarthritis: current knowledge and future perspectives. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie. 2019; 109: 2318‐ 2326. 30551490
- [131]McGonagle D, Baboolal TG, Jones E. Native joint‐resident mesenchymal stem cells for cartilage repair in osteoarthritis. Nat Rev Rheumatol. 2017; 13: 719‐ 730. 29118440
- [132]Xue K, Zhang X, Gao Z, Xia W, Qi L, Liu K. Cartilage progenitor cells combined with PHBV in cartilage tissue engineering. J Transl Med. 2019; 17: 104. 30925884 PMC6441183
- [133]Zhang S, Hamid MR, Wang T, et al. RSK‐3 promotes cartilage regeneration via interacting with rpS6 in cartilage stem/progenitor cells. Theranostics. 2020; 10: 6915‐ 6927. 32550912 PMC7295041
- [134]Delplace V, Boutet MA, Le Visage C, Maugars Y, Guicheux J, Vinatier C. Osteoarthritis: from upcoming treatments to treatments yet to come. Joint Bone Spine. 2021; 88: 105206. 33962030
- [135]Hodgkinson T, Kelly DC, Curtin CM, O'Brien FJ. Mechanosignalling in cartilage: an emerging target for the treatment of osteoarthritis. Nat Rev Rheumatol. 2022; 18: 67‐ 84. 34934171
- [137]Dernie F, Adeyoju D. A matter of time: circadian clocks in osteoarthritis and the potential of chronotherapy. Exp Gerontol. 2021; 143: 111163. 33227402
- [138]Soul J, Dunn SL, Anand S, et al. Stratification of knee osteoarthritis: two major patient subgroups identified by genome‐wide expression analysis of articular cartilage. Ann Rheum Dis. 2018; 77: 423. 29273645 PMC5867416
- [139]Zhu S, Kuek V, Bennett S, Xu H, Rosen V, Xu J. Protein Cytl1: its role in chondrogenesis, cartilage homeostasis, and disease. Cell Mol Life Sci. 2019; 76: 3515‐ 3523. 31089746 PMC6697716
- [140]Sanchez C, Mazzucchelli G, Lambert C, Comblain F, DePauw E, Henrotin Y. Comparison of secretome from osteoblasts derived from sclerotic versus non‐sclerotic subchondral bone in OA: a pilot study. PLoS One. 2018; 13: e0194591. 29547667 PMC5856400
- [141]Makris EA, Hadidi P, Athanasiou KA. The knee meniscus: structure‐function, pathophysiology, current repair techniques, and prospects for regeneration. Biomaterials. 2011; 32: 7411‐ 7431. 21764438 PMC3161498
- [142]Zellner J, Pattappa G, Koch M, et al. Autologous mesenchymal stem cells or meniscal cells: what is the best cell source for regenerative meniscus treatment in an early osteoarthritis situation? Stem Cell Res Ther. 2017; 8: 225. 29017608 PMC5634903
- [143]Lee KI, Gamini R, Olmer M, et al. Mohawk is a transcription factor that promotes meniscus cell phenotype and tissue repair and reduces osteoarthritis severity. Sci Transl Med. 2020; 12(567):eaan7967. PMC7955769 33115953
- [144]Song H, Guo T, Zhao Z, et al. Biocompatible PEGylated gold nanorods function As cytokinesis inhibitors to suppress angiogenesis. Biomaterials. 2018; 178: 23‐ 35. 29908342
- [146]Sun S, Liu H, Hu Y, et al. Selection and identification of a novel ssDNA aptamer targeting human skeletal muscle. Bioact Mater. 2023; 20: 166‐ 178. 35663338 PMC9157180
- [147]Yellen BB, Zawistowski JS, Czech EA, et al. Massively parallel quantification of phenotypic heterogeneity in single‐cell drug responses. Sci Adv. 2021; 7: eabf9840. 34533995 PMC8448449
- [148]Chen S, Chen X, Geng Z, Su J. The horizon of bone organoid: a perspective on construction and application. Bioact Mater. 2022; 18: 15‐ 25. 35387160 PMC8961298
- [149]Kim D, Kobayashi T, Voisin B, et al. Targeted therapy guided by single‐cell transcriptomic analysis in drug‐induced hypersensitivity syndrome: a case report. Nat Med. 2020; 26: 236‐ 243. 31959990 PMC7105105
- [152]Castellanos‐Rueda R, Di Roberto RB, Schlatter FS, Reddy ST. Leveraging single‐cell sequencing for chimeric antigen receptor T cell therapies. Trends Biotechnol. 2021; 39: 1308‐ 1320. 33832782
- [153]Montoya C, Du Y, Gianforcaro AL, Orrego S, Yang M, Lelkes PI. On the road to smart biomaterials for bone research: definitions, concepts, advances, and outlook. Bone Res. 2021; 9: 12. 33574225 PMC7878740
- [154]Sun J, Yin Z, Wang X, Su J. Exosome‐laden hydrogels: a novel cell‐free strategy for In‐situ bone tissue regeneration. Front Bioeng Biotechnol. 2022; 10: 866208. 35433664 PMC9011111
- [155]Meng F, Yin Z, Ren X, Geng Z, Su J. Construction of local drug delivery system on titanium‐based implants to improve Osseointegration. Pharmaceutics. 2022; 14(5):1069. PMC9146791 35631656
- [156]Wang Z, Li M, Yu B, Cao L, Yang Q, Su J. Nanocalcium‐deficient hydroxyapatite‐poly (e‐caprolactone)‐polyethylene glycol‐poly (e‐caprolactone) composite scaffolds. Int J Nanomedicine. 2012; 7: 3123‐ 3131. 22848159 PMC3405873
- [157]Huang J, Fan C, Chen Y, et al. Single‐cell RNA‐seq reveals functionally distinct biomaterial degradation‐related macrophage populations. Biomaterials. 2021; 277: 121116. 34478932
- [158]Guo P, Liu X, Zhang P, et al. A single‐cell transcriptome of mesenchymal stromal cells to fabricate bioactive hydroxyapatite materials for bone regeneration. Bioact Mater. 2022; 9: 281‐ 298. 34820571 PMC8586438
- [159]Xie C, Liang R, Ye J, et al. High‐efficient engineering of osteo‐callus organoids for rapid bone regeneration within one month. Biomaterials. 2022; 288: 121741. 36031458
- [160]Grandi FC, Baskar R, Smeriglio P, et al. Single‐cell mass cytometry reveals cross‐talk between inflammation‐dampening and inflammation‐amplifying cells in osteoarthritic cartilage. Sci Adv. 2020; 6: eaay5352. 32201724 PMC7069698
- [161]Shao H, Ge M, Zhang J, Zhao T, Zhang S. Osteoclasts differential‐related prognostic biomarker for osteosarcoma based on single cell, bulk cell and gene expression datasets. BMC Cancer. 2022; 22: 288. 35300639 PMC8932072
- [162]Zeng Z, Li W, Zhang D, et al. Development of a Chemoresistant risk scoring model for Prechemotherapy osteosarcoma using single‐cell sequencing. Front Oncol. 2022; 12: 893282. 35664733 PMC9159767
- [163]Soul J, Barter MJ, Little CB, Young DA. OATargets: a knowledge base of genes associated with osteoarthritis joint damage in animals. Ann Rheum Dis. 2021; 80: 376‐ 383. 33077471 PMC7892386
- [164]Stuart T, Satija R. Integrative single‐cell analysis. Nat Rev Genet. 2019; 20: 257‐ 272. 30696980
- [165]Ranzoni AM, Tangherloni A, Berest I, et al. Integrative single‐cell RNA‐Seq and ATAC‐Seq analysis of human developmental hematopoiesis. Cell Stem Cell. 2021; 28: 472‐ 487.e477. 33352111 PMC7939551
- [166]Parker E, Hofer IMJ, Rice SJ, et al. Multi‐tissue epigenetic and gene expression analysis combined with epigenome modulation identifies RWDD2B as a target of osteoarthritis susceptibility. Arthritis Rheumatol. 2021; 73: 100‐ 109. 32755071
- [167]Rice SJ, Beier F, Young DA, Loughlin J. Interplay between genetics and epigenetics in osteoarthritis. Nat Rev Rheumatol. 2020; 16: 268‐ 281. 32273577
- [168]Briggs MT, Kuliwaba JS, Muratovic D, et al. MALDI mass spectrometry imaging of N‐glycans on tibial cartilage and subchondral bone proteins in knee osteoarthritis. Proteomics. 2016; 16: 1736‐ 1741. 26992165
- [169]Spitzer MH, Nolan GP. Mass cytometry: single cells, many features. Cell. 2016; 165: 780‐ 791. 27153492 PMC4860251
- [170]Othman Z, Cillero Pastor B, van Rijt S, Habibovic P. Understanding interactions between biomaterials and biological systems using proteomics. Biomaterials. 2018; 167: 191‐ 204. 29571054
- [171]Liu Y, Yang M, Deng Y, et al. High‐spatial‐resolution multi‐omics sequencing via deterministic barcoding in tissue. Cell. 2020; 183: 1665‐ 1681.e1618. 33188776 PMC7736559
- [172]Lei Y, Tang R, Xu J, et al. Applications of single‐cell sequencing in cancer research: progress and perspectives. J Hematol Oncol. 2021; 14: 91. 34108022 PMC8190846
- [173]Regner MJ, Wisniewska K, Garcia‐Recio S, et al. A multi‐omic single‐cell landscape of human gynecologic malignancies. Mol Cell. 2021; 81: 4924‐ 4941.e4910. 34739872 PMC8642316
- [174]He X, Memczak S, Qu J, Belmonte JCI, Liu GH. Single‐cell omics in ageing: a young and growing field. Nat Metab. 2020; 2: 293‐ 302. 32694606
- [175]Lodato MA, Rodin RE, Bohrson CL, et al. Aging and neurodegeneration are associated with increased mutations in single human neurons. Science. 2018; 359: 555‐ 559. 29217584 PMC5831169
- [176]Steinberg J, Brooks RA, Southam L, et al. Widespread epigenomic, transcriptomic and proteomic differences between hip osteophytic and articular chondrocytes in osteoarthritis. Rheumatology (Oxford). 2018; 57: 1481‐ 1489. 29741735 PMC6055583
- [177]Ratneswaran A, Rockel JS, Kapoor M. Understanding osteoarthritis pathogenesis: a multiomics system‐based approach. Curr Opin Rheumatol. 2020; 32: 80‐ 91. 31724972
- [178]Ma A, McDermaid A, Xu J, Chang Y, Ma Q. Integrative methods and practical challenges for single‐cell multi‐omics. Trends Biotechnol. 2020; 38: 1007‐ 1022. 32818441 PMC7442857
- [179]Kiselev VY, Andrews TS, Hemberg M. Challenges in unsupervised clustering of single‐cell RNA‐seq data. Nat Rev Genet. 2019; 20: 273‐ 282. 30617341
- [180]Rai MF, Wu CL, Capellini TD, et al. Single cell omics for musculoskeletal research. Curr Osteoporos Rep. 2021; 19: 131‐ 140. 33559841 PMC8743139
Cited by
Sorted by citations
Advancing osteoarthritis research: The role of AI in clinical, imaging and omics fields
Ou, J., Zhang, J., Alswadeh, M., Zhu, Z., Tang, J., Sang, H., & Lu, K. (2025) · Bone Research · doi:10.1038/s41413-025-00423-2 · Cited by 61 · see citing works
Biomarker-Guided Imaging and AI-Augmented Diagnosis of Degenerative Joint Disease
Kumar, R., Sporn, K., Borole, A., Khanna, A., Gowda, C., Paladugu, P., Ngo, A., Jagadeesan, R., Zaman, N., & Tavakkoli, A. (2025) · Diagnostics · doi:10.3390/diagnostics15111418 · Cited by 10 · see citing works
“…transcriptomics provide an unprecedented resolution of cellular heterogeneity, revealing distinct cell subpopulations and molecular signatures in joint tissues that drive pathogenesis, offering potential cellular biomarkers for precise disease classification and targeted therapies [159,160].”
- Authors
- Gu, Y., Hu, Y., Zhang, H., Wang, S., Xu, K., & Su, J.
- Affiliations
- Shanghai University (CN)
- Corresponding author
- Wang, Sicheng
- Xu, Ke
- Su, Jiacan
- Venue
- Cell Proliferation
- Publisher
- Wiley
- Published
- 2023-06-14
- Volume
- 56
- Issue
- 12
- Pages
- e13517-e13517
- ISSN
- 0960-7722 (ISSN-L)
- 1365-2184
- PMC
- PMC10693192
- OpenAlex
- W4380730812
- Cited by
- 59
- References
- 9
- Citations by year
- 2026: 18 · 2025: 31 · 2024: 9 · 2023: 1
- FWCI
- 2.58
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Proliferation (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (82172098)
- Topics
- Health Sciences › Medicine › Rheumatology › Osteoarthritis Treatment and Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone and Joint Diseases
- Keywords
- osteoarthritis, single-cell RNA sequencing, articular cartilage, meniscus, synovium, subchondral bone, chondrocytes, osteoblasts, fibroblasts, endothelial cells, cell crosstalk, disease heterogeneity, therapeutic target, tissue engineering, personalized medicine, multi-omics
- MeSH terms
- Bone and Bones, Cartilage, Articular, Humans, Osteoarthritis, Sequence Analysis, RNA, Chondrocytes, Endothelial Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review