CoChat
Sign Up
Cited by 50Rheumatoid Arthritis Research and TherapiesNatural Compounds in Disease TreatmentExtracellular vesicles in disease

Immunomodulatory matrix-bound nanovesicles mitigate acute and chronic pristane-induced rheumatoid arthritis

Open access
Crum, Raphael J., Hall, Kelsey, Molina, Catalina Pineda, Hussey, George S., Graham, Emma, Li, Hongshuai, Badylak, Stephen F.·2022·npj Regenerative Medicine
DOI 10.1038/s41536-022-00208-9PMC PMC8810774
Open this paper in CoChat — free accountOpen PDF

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and destruction of synovial joints affecting ~7.5 million people worldwide. Disease pathology is driven by an imbalance in the ratio of pro-inflammatory vs. anti-inflammatory immune cells, especially macrophages. Modulation of macrophage phenotype, specifically an M1 to M2, pro- to anti-inflammatory transition, can be induced by biologic scaffold materials composed of extracellular matrix (ECM). The ECM-based immunomodulatory effect is thought to be mediated in part through recently identified matrix-bound nanovesicles (MBV) embedded within ECM. Isolated MBV was delivered via intravenous (i.v.) or peri-articular (p.a.) injection to rats with pristane-induced arthritis (PIA). The results of MBV administration were compared to intraperitoneal (i.p.) administration of methotrexate (MTX), the clinical standard of care. Relative to the diseased animals, i.p. MTX, i.v. MBV, and p.a. MBV reduced arthritis scores in both acute and chronic pristane-induced arthritis, decreased synovial inflammation, decreased adverse joint remodeling, and reduced the ratio of synovial and splenic M1 to M2 macrophages (p < 0.05). Both p.a. and i.v. MBV reduced the serum concentration of RA and PIA biomarkers CXCL10 and MCP-3 in the acute and chronic phases of disease (p < 0.05). Flow-cytometry revealed the presence of a systemic CD43hi/His48lo/CD206+, immunoregulatory monocyte population unique to p.a. and i.v. MBV treatment associated with disease resolution. The results show that the therapeutic efficacy of MBV is equal to that of MTX for the management of acute and chronic pristane-induced arthritis and, further, this effect is associated with modulation of local synovial macrophages and systemic myeloid populations.

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.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41536-022-00208-9

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.

A few free checks a day · papers already verified open instantly · results are public

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?

  • The effects of immune modulation after MBV injection seem to have a persistent effect on the immune system, suggesting an epigenetic effect.

    “What is more, the effects of the immune modulation after MBV injection seem to have a persistent effect on the immune system [76,77], suggesting an epigenetic effect.”

    From Immune Response to Extracellular Matrix Bioscaffolds: A Comprehensive Review (2025) · cites this paper as [76]

    The Results report that MBV-treated rats did not relapse through day 100, despite receiving no further treatment after day 28. The paper also reports changes in immune-cell populations, but it does not show that those immune changes persisted after treatment or identify an epigenetic mechanism; the Discussion says the molecular mechanisms remain unclear. No page numbers are available in our copy. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Injection of MBV can cause immune modulation locally and systemically.

    “Recent studies have shown that the injection of MBV can cause immune modulation locally [164,165] and systemically [76,168].”

    From Immune Response to Extracellular Matrix Bioscaffolds: A Comprehensive Review (2025) · cites this paper as [76]

  • ECM bioscaffold immune regulation is not only at the local level but also systemic.

    “research indicates that this immune regulation is not only at the local level, but also systemic, as suggested in studies with decellularized tissues [57,58], or MBV [76,168,197]”

    From Immune Response to Extracellular Matrix Bioscaffolds: A Comprehensive Review (2025) · cites this paper as [76]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

The citation lists haven’t been fetched yet

References 106 · Cited by 50

Research works printed but not linked: 88

  1. [2]Badylak SF Freytes DO Gilbert TW Extracellular matrix as a biological scaffold material: structure and function Acta Biomater. 2009 5 1 13 18938117
  2. [3]Bissell MJ Hall HG Parry G How does the extracellular matrix direct gene expression? J. Theor. Biol. 1982 99 31 68 6892044
  3. [4]Brown BN Macrophage phenotype as a predictor of constructive remodeling following the implantation of biologically derived surgical mesh materials Acta Biomater. 2012 8 978 987 22166681 PMC4325370
  4. [5]Dziki JL Solubilized extracellular matrix bioscaffolds derived from diverse source tissues differentially influence macrophage phenotype J. Biomed. Mater. Res. A 2017 105 138 147 27601305
  5. [6]Petrosyan A A step towards clinical application of acellular matrix: a clue from macrophage polarization Matrix Biol. 2017 57–58 334 346 27575985 PMC6717660
  6. [8]Keane TJ Restoring mucosal barrier function and modifying macrophage phenotype with an extracellular matrix hydrogel: potential therapy for ulcerative colitis J. Crohns Colitis 2017 11 360 368 27543807
  7. [9]Huleihel L Matrix-bound nanovesicles within ECM bioscaffolds Sci. Adv. 2016 2 e1600502 27386584 PMC4928894
  8. [14]Naranjo JD Esophageal extracellular matrix hydrogel mitigates metaplastic change in a dog model of Barrett’s esophagus Sci. Adv. 2020 6 eaba4526 32656339 PMC7329334
  9. [15]Saldin LT The effect of normal, metaplastic, and neoplastic esophageal extracellular matrix upon macrophage activation J. Immunol. Regen. Med 2021 13 100037 34027260 PMC8136242
  10. [16]Meng FW Slivka PF Dearth CL Badylak SF Solubilized extracellular matrix from brain and urinary bladder elicits distinct functional and phenotypic responses in macrophages Biomaterials 2015 46 131 140 25678122
  11. [17]Ploeger DTA van Putten SM Koerts JA van Luyn MJA Harmsen MC Human macrophages primed with angiogenic factors show dynamic plasticity, irrespective of extracellular matrix components Immunobiology 2012 217 299 306 22093249
  12. [18]Londono R Badylak SF Biologic scaffolds for regenerative medicine: mechanisms of in vivo remodeling Ann. Biomed. Eng. 2015 43 577 592 25213186
  13. [19]Badylak SF The extracellular matrix as a biologic scaffold material Biomaterials 2007 28 3587 3593 17524477
  14. [20]Hussey GS Lipidomics and RNA sequencing reveal a novel subpopulation of nanovesicle within extracellular matrix biomaterials Sci. Adv. 2020 6 eaay4361 32219161 PMC7083606
  15. [21]van der Merwe Y Faust AE Steketee MB Matrix bound vesicles and miRNA cargoes are bioactive factors within extracellular matrix bioscaffolds Neural Regen. Res. 2017 12 1597 1599 29171416 PMC5696832
  16. [22]Zhu W Anti-citrullinated protein antibodies induce macrophage subset disequilibrium in RA patients Inflammation 2015 38 2067 2075 26063186
  17. [23]Fukui S M1 and M2 monocytes in rheumatoid arthritis: a contribution of imbalance of M1/M2 monocytes to osteoclastogenesis Front. Immunol. 2017 8 1958 29375576 PMC5766997
  18. [24]Kennedy A Fearon U Veale DJ Godson C Macrophages in synovial inflammation Front. Immunol. 2011 2 52 22566842 PMC3342259
  19. [25]Feldmann M Brennan FM Maini RN Role of cytokines in rheumatoid arthritis Annu. Rev. Immunol. 1996 14 397 440 8717520
  20. [26]Iwamoto T Okamoto H Toyama Y Momohara S Molecular aspects of rheumatoid arthritis: chemokines in the joints of patients FEBS J. 2008 275 4448 4455 18662305
  21. [27]Smolen JS Rheumatoid arthritis Nat. Rev. Dis. Prim. 2018 4 18001 29417936
  22. [28]Feldmann M Brennan FM Maini RN Rheumatoid arthritis Cell 1996 85 307 310 8616886
  23. [29]Iguchi T Kurosaka M Ziff M Electron microscopic study of HLA-DR and monocyte/macrophage staining cells in the rheumatoid synovial membrane Arthritis Rheum. 1986 29 600 613 2424458
  24. [30]Siouti E Andreakos E The many facets of macrophages in rheumatoid arthritis Biochem. Pharmacol. 2019 165 152 169 30910693
  25. [31]Kinne RW Bräuer R Stuhlmüller B Palombo-Kinne E Burmester GR Macrophages in rheumatoid arthritis Arthritis Res. 2000 2 189 202 11094428 PMC130001
  26. [32]Cauli A Yanni G Panayi GS Interleukin-1, interleukin-1 receptor antagonist and macrophage populations in rheumatoid arthritis synovial membrane Br. J. Rheumatol. 1997 36 935 940 9376987
  27. [33]Ridley MG Kingsley G Pitzalis C Panayi GS Monocyte activation in rheumatoid arthritis: evidence for in situ activation and differentiation in joints Br. J. Rheumatol. 1990 29 84 88 1691032
  28. [34]Sun W Targeting notch-activated M1 macrophages attenuates joint tissue damage in a mouse model of inflammatory arthritis J. Bone Miner. Res. 2017 32 1469 1480 28256007 PMC5489377
  29. [35]Kinne RW Stuhlmüller B Burmester G-R Cells of the synovium in rheumatoid arthritis. Macrophages Arthritis Res. Ther. 2007 9 224 18177511 PMC2246244
  30. [37]Kuan WP CXCL 9 and CXCL 10 as sensitive markers of disease activity in patients with rheumatoid arthritis J. Rheumatol. 2010 37 257 264 20032101
  31. [38]Lee J-H Pathogenic roles of CXCL10 signaling through CXCR3 and TLR4 in macrophages and T cells: relevance for arthritis Arthritis Res. Ther. 2017 19 163 28724396 PMC5518115
  32. [39]Katschke KJ Differential expression of chemokine receptors on peripheral blood, synovial fluid, and synovial tissue monocytes/macrophages in rheumatoid arthritis Arthritis Rheum. 2001 44 1022 1032 11352233
  33. [40]Szekanecz Z Vegvari A Szabo Z Koch AE Chemokines and chemokine receptors in arthritis Front. Biosci. (Sch. Ed.) 2010 2 153 167 PMC2917905 20036936
  34. [41]Bankhead P QuPath: open source software for digital pathology image analysis Sci. Rep. 2017 7 16878 29203879 PMC5715110
  35. [43]Badylak SF Extracellular matrix and the immune system: friends or foes Nat. Rev. Urol. 2019 16 389 390 31110274
  36. [44]Badylak SF Biologic scaffolds for constructive tissue remodeling Biomaterials 2011 32 316 319 21125721
  37. [46]Agrawal V Epimorphic regeneration approach to tissue replacement in adult mammals Proc. Natl Acad. Sci. USA 2010 107 3351 3355 19966310 PMC2840465
  38. [47]Allman AJ Xenogeneic extracellular matrix grafts elicit a TH2-restricted immune response Transplantation 2001 71 1631 1640 11435976
  39. [48]Beattie AJ Gilbert TW Guyot JP Yates AJ Badylak SF Chemoattraction of progenitor cells by remodeling extracellular matrix scaffolds Tissue Eng. Part A 2009 15 1119 1125 18837648 PMC2789572
  40. [51]Badylak SF Dziki JL Sicari BM Ambrosio F Boninger ML Mechanisms by which acellular biologic scaffolds promote functional skeletal muscle restoration Biomaterials 2016 103 128 136 27376561
  41. [52]van der Merwe Y Matrix-bound nanovesicles prevent ischemia-induced retinal ganglion cell axon degeneration and death and preserve visual function Sci. Rep. 2019 9 3482 30837658 PMC6400956
  42. [53]Sicari BM An acellular biologic scaffold promotes skeletal muscle formation in mice and humans with volumetric muscle loss Sci. Transl. Med. 2014 6 234ra58 24786326 PMC5942588
  43. [54]Sicari BM A murine model of volumetric muscle loss and a regenerative medicine approach for tissue replacement Tissue Eng. Part A 2012 18 1941 1948 22906411 PMC3463275
  44. [56]Turner NJ Badylak JS Weber DJ Badylak SF Biologic scaffold remodeling in a dog model of complex musculoskeletal injury J. Surg. Res. 2012 176 490 502 22341350
  45. [57]Friedman B Cronstein B Methotrexate mechanism in treatment of rheumatoid arthritis Jt. Bone Spine 2019 86 301 307 PMC6360124 30081197
  46. [58]Ahuja V Miller SE Howell DN Identification of two subpopulations of rat monocytes expressing disparate molecular forms and quantities of CD43 Cell Immunol. 1995 163 59 69 7758131
  47. [59]Thomas G Tacke R Hedrick CC Hanna RN Nonclassical patrolling monocyte function in the vasculature Arterioscler. Thromb. Vasc. Biol. 2015 35 1306 1316 25838429 PMC4441550
  48. [60]Barnett-Vanes A Sharrock A Birrell MA Rankin S A single 9-colour flow cytometric method to characterise major leukocyte populations in the rat: validation in a model of LPS-induced pulmonary inflammation PLoS ONE 2016 11 e0142520 26764486 PMC4713146
  49. [61]Misharin AV Nonclassical Ly6C(−) monocytes drive the development of inflammatory arthritis in mice Cell Rep. 2014 9 591 604 25373902 PMC4223808
  50. [62]Vingsbo C Pristane-induced arthritis in rats: a new model for rheumatoid arthritis with a chronic disease course influenced by both major histocompatibility complex and non-major histocompatibility complex genes Am. J. Pathol. 1996 149 1675 1683 8909256 PMC1865278
  51. [63]Hoffmann MH The rheumatoid arthritis-associated autoantigen hnRNP-A2 (RA33) is a major stimulator of autoimmunity in rats with pristane-induced arthritis J. Immunol. 2007 179 7568 7576 18025202
  52. [64]Tuncel J Animal models of rheumatoid arthritis (I): pristane-induced arthritis in the rat PLoS ONE 2016 11 e0155936 27227821 PMC4881957
  53. [65]Huber LC Synovial fibroblasts: key players in rheumatoid arthritis Rheumatology 2006 45 669 675 16567358
  54. [66]Yang C Robbins PD Immunosuppressive exosomes: a new approach for treating arthritis Int. J. Rheumatol. 2012 2012 573528 22548070 PMC3324137
  55. [67]Kim S-H Exosomes derived from IL-10-treated dendritic cells can suppress inflammation and collagen-induced arthritis J. Immunol. 2005 174 6440 6448 15879146
  56. [68]Ruffner MA B7-1/2, but not PD-L1/2 molecules, are required on IL-10-treated tolerogenic DC and DC-derived exosomes for in vivo function Eur. J. Immunol. 2009 39 3084 3090 19757438 PMC3075967
  57. [69]Kim SH Bianco NR Shufesky WJ Morelli AE Robbins PD Effective treatment of inflammatory disease models with exosomes derived from dendritic cells genetically modified to express IL-4 J. Immunol. 2007 179 2242 2249 17675485
  58. [70]Kim SH Exosomes derived from genetically modified DC expressing FasL are anti-inflammatory and immunosuppressive Mol. Ther. 2006 13 289 300 16275099
  59. [71]Bianco NR Kim SH Ruffner MA Robbins PD Therapeutic effect of exosomes from indoleamine 2,3-dioxygenase-positive dendritic cells in collagen-induced arthritis and delayed-type hypersensitivity disease models Arthritis Rheum. 2009 60 380 389 19180475 PMC3491653
  60. [72]Kim SH Bianco NR Shufesky WJ Morelli AE Robbins PD MHC class II+ exosomes in plasma suppress inflammation in an antigen-specific and Fas ligand/Fas-dependent manner J. Immunol. 2007 179 2235 2241 17675484
  61. [74]Schulze-Koops H Kalden JR The balance of Th1/Th2 cytokines in rheumatoid arthritis Best. Pract. Res. Clin. Rheumatol. 2001 15 677 691 11812015
  62. [75]Roberts CA Dickinson AK Taams LS The interplay between monocytes/macrophages and CD4(+) T cell subsets in rheumatoid arthritis Front. Immunol. 2015 6 571 26635790 PMC4652039
  63. [76]Walter GJ Interaction with activated monocytes enhances cytokine expression and suppressive activity of human CD4+CD45ro+CD25+CD127(low) regulatory T cells Arthritis Rheum. 2013 65 627 638 23280063 PMC3947722
  64. [77]Evans HG In vivo activated monocytes from the site of inflammation in humans specifically promote Th17 responses Proc. Natl Acad. Sci. USA 2009 106 6232 6237 19325128 PMC2669354
  65. [78]van Amelsfort JMR Proinflammatory mediator-induced reversal of CD4+,CD25+ regulatory T cell-mediated suppression in rheumatoid arthritis Arthritis Rheum. 2007 56 732 742 17328044
  66. [79]Köller M Expression of adhesion molecules on synovial fluid and peripheral blood monocytes in patients with inflammatory joint disease and osteoarthritis Ann. Rheum. Dis. 1999 58 709 712 10531076 PMC1752805
  67. [80]Müller-Ladner U Ospelt C Gay S Distler O Pap T Cells of the synovium in rheumatoid arthritis. Synovial fibroblasts Arthritis Res. Ther. 2007 9 223 18177509 PMC2246247
  68. [81]Pretzel D Pohlers D Weinert S Kinne RW In vitro model for the analysis of synovial fibroblast-mediated degradation of intact cartilage Arthritis Res. Ther. 2009 11 R25 19226472 PMC2688258
  69. [82]Danks L RANKL expressed on synovial fibroblasts is primarily responsible for bone erosions during joint inflammation Ann. Rheum. Dis. 2016 75 1187 1195 26025971
  70. [83]Kramer I Wibulswas A Croft D Genot E Rheumatoid arthritis: targeting the proliferative fibroblasts Prog. Cell Cycle Res. 2003 5 59 70 14593701
  71. [84]Pap T Müller-Ladner U Gay RE Gay S Fibroblast biology. Role of synovial fibroblasts in the pathogenesis of rheumatoid arthritis Arthritis Res. 2000 2 361 367 11094449 PMC130137
  72. [85]Odobasic D Formyl peptide receptor activation inhibits the expansion of effector T cells and synovial fibroblasts and attenuates joint injury in models of rheumatoid arthritis Int. Immunopharmacol. 2018 61 140 149 29879657
  73. [86]Pap T Cinski A Baier A Gay S Meinecke I Modulation of pathways regulating both the invasiveness and apoptosis in rheumatoid arthritis synovial fibroblasts Jt. Bone Spine: Rev. Rhum. 2003 70 477 479 14667557
  74. [87]Andreas K Key regulatory molecules of cartilage destruction in rheumatoid arthritis: an in vitro study Arthritis Res. Ther. 2008 10 R9 18205922 PMC2374452
  75. [88]Korb-Pap A Early structural changes in cartilage and bone are required for the attachment and invasion of inflamed synovial tissue during destructive inflammatory arthritis Ann. Rheum. Dis. 2012 71 1004 1011 22258493
  76. [89]Meyer L-H Franssen L Pap T The role of mesenchymal cells in the pathophysiology of inflammatory arthritis Best. Pract. Res. Clin. Rheumatol. 2006 20 969 981 16980218
  77. [90]Donlin LT Jayatilleke A Giannopoulou EG Kalliolias GD Ivashkiv LB Modulation of TNF-induced macrophage polarization by synovial fibroblasts J. Immunol. 2014 193 2373 2383 25057003 PMC4135020
  78. [91]Rengel Y Ospelt C Gay S Proteinases in the joint: clinical relevance of proteinases in joint destruction Arthritis Res. Ther. 2007 9 221 18001502 PMC2212555
  79. [92]Burrage PS Mix KS Brinckerhoff CE Matrix metalloproteinases: role in arthritis Front. Biosci. 2006 11 529 543 16146751
  80. [93]Page-McCaw A Ewald AJ Werb Z Matrix metalloproteinases and the regulation of tissue remodelling Nat. Rev. Mol. Cell Biol. 2007 8 221 233 17318226 PMC2760082
  81. [94]McInnes IB Schett G Cytokines in the pathogenesis of rheumatoid arthritis Nat. Rev. Immunol. 2007 7 429 442 17525752
  82. [95]Catterall JB Synergistic induction of matrix metalloproteinase 1 by interleukin-1alpha and oncostatin M in human chondrocytes involves signal transducer and activator of transcription and activator protein 1 transcription factors via a novel mechanism Arthritis Rheum. 2001 44 2296 2310 11665970
  83. [96]Eberhardt W Huwiler A Beck KF Walpen S Pfeilschifter J Amplification of IL-1 beta-induced matrix metalloproteinase-9 expression by superoxide in rat glomerular mesangial cells is mediated by increased activities of NF-kappa B and activating protein-1 and involves activation of the mitogen-activated protein kinase pathways J. Immunol. 2000 165 5788 5797 11067938
  84. [97]Wei S Kitaura H Zhou P Ross FP Teitelbaum SL IL-1 mediates TNF-induced osteoclastogenesis J. Clin. Investig. 2005 115 282 290 15668736 PMC544608
  85. [98]Dayer J-M Bresnihan B Targeting interleukin-1 in the treatment of rheumatoid arthritis Arthritis Rheum. 2002 46 574 578 11920390
  86. [99]Eriksson K Effects by periodontitis on pristane-induced arthritis in rats J. Transl. Med. 2016 14 311 27809921 PMC5094068
  87. [100]Seeuws S A multiparameter approach to monitor disease activity in collagen-induced arthritis Arthritis Res. Ther. 2010 12 R160 20731827 PMC2945063
  88. [101]McQuin C CellProfiler 3.0: next-generation image processing for biology PLoS Biol. 2018 16 e2005970 29969450 PMC6029841

Authors
Crum, R. J., Hall, K., Molina, C. P., Hussey, G. S., Graham, E., Li, H., & Badylak, S. F.
Affiliations
  • University of Pittsburgh (US)
  • University of Iowa (US)
Corresponding author
Badylak, Stephen F.
ORCID
Venue
npj Regenerative Medicine
Publisher
Springer Science and Business Media LLC
Published
2022-02-02
Volume
7
Issue
1
Pages
13-13
ISSN
2057-3995 (ISSN-L)
DOI
10.1038/s41536-022-00208-9
PMC
PMC8810774
OpenAlex
W4210351827
Cited by
50
References
106
Citations by year
2026: 10 · 2025: 13 · 2024: 13 · 2023: 9 · 2022: 5
FWCI
7.28
Type
journal article
Language
en
Open access
Licence
Locations
  • npj Regenerative Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences (TL1 TR001858)
Topics
  • Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
  • Health Sciences › Medicine › Complementary and alternative medicine › Natural Compounds in Disease Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
Keywords
rheumatoid arthritis, pristane-induced arthritis, extracellular matrix, macrophage polarization, M1/M2 macrophages, immunomodulation, intravenous delivery, methotrexate, synovitis, joint remodeling, CXCL10, MCP-3, biomarkers

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