{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T21:17:22Z","timestamp":1793222242912,"version":"4.5.0"},"reference-count":79,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2024,3,10]],"date-time":"2024-03-10T00:00:00Z","timestamp":1710028800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["5R21AR080388-02"],"award-info":[{"award-number":["5R21AR080388-02"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>During the progression of knee osteoarthritis (OA), the synovium and infrapatellar fat pad (IFP) can serve as source for Substance P (SP) and calcitonin gene-related peptide (CGRP), two important pain-transmitting, immune, and inflammation modulating neuropeptides. Our previous studies showed that infrapatellar fat pad-derived mesenchymal stem\/stromal cells (MSC) acquire a potent immunomodulatory phenotype and actively degrade Substance P via CD10 both in vitro and in vivo. On this basis, our hypothesis is that CD10-bound IFP-MSC sEVs can be engineered to target CGRP while retaining their anti-inflammatory phenotype. Herein, human IFP-MSC cultures were transduced with an adeno-associated virus (AAV) vector carrying a GFP-labelled gene for a CGRP antagonist peptide (aCGRP). The GFP positive aCGRP IFP-MSC were isolated and their sEVs\u2019 miRNA and protein cargos were assessed using multiplex methods. Our results showed that purified aCGRP IFP-MSC cultures yielded sEVs with cargo of 147 distinct MSC-related miRNAs. Reactome analysis of miRNAs detected in these sEVs revealed strong involvement in the regulation of target genes involved in pathways that control pain, inflammation and cartilage homeostasis. Protein array of the sEVs cargo demonstrated high presence of key immunomodulatory and reparative proteins. Stimulated macrophages exposed to aCGRP IFP-MSC sEVs demonstrated a switch towards an alternate M2 status. Also, stimulated cortical neurons exposed to aCGRP IFP-MSC sEVs modulate their molecular pain signaling profile. Collectively, our data suggest that yielded sEVs can putatively target CGRP in vivo, while containing potent anti-inflammatory and analgesic cargo, suggesting the promise for novel sEVs-based therapeutic approaches to diseases such as OA.<\/jats:p>","DOI":"10.3390\/cells13060484","type":"journal-article","created":{"date-parts":[[2024,3,11]],"date-time":"2024-03-11T07:25:32Z","timestamp":1710141932000},"page":"484","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Modification of Mesenchymal Stem\/Stromal Cell-Derived Small Extracellular Vesicles by Calcitonin Gene Related Peptide (CGRP) Antagonist: Potential Implications for Inflammation and Pain Reversal"],"prefix":"10.3390","volume":"13","author":[{"given":"Kevin","family":"Liebmann","sequence":"first","affiliation":[{"name":"Department of Orthopedics, UHealth Sports Medicine Institute, Miller School of Medicine, University of Miami, Miami, FL 33146, USA"},{"name":"Diabetes Research Institute & Cell Transplant Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA"},{"name":"Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario A.","family":"Castillo","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, UHealth Sports Medicine Institute, Miller School of Medicine, University of Miami, Miami, FL 33146, USA"},{"name":"Diabetes Research Institute & Cell Transplant Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9096-7770","authenticated-orcid":false,"given":"Stanislava","family":"Jergova","sequence":"additional","affiliation":[{"name":"Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas M.","family":"Best","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, UHealth Sports Medicine Institute, Miller School of Medicine, University of Miami, Miami, FL 33146, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9742-7240","authenticated-orcid":false,"given":"Jacqueline","family":"Sagen","sequence":"additional","affiliation":[{"name":"Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3892-9013","authenticated-orcid":false,"given":"Dimitrios","family":"Kouroupis","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, UHealth Sports Medicine Institute, Miller School of Medicine, University of Miami, Miami, FL 33146, USA"},{"name":"Diabetes Research Institute & Cell Transplant Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.ejpain.2005.12.011","article-title":"Localization of SP-and CGRP-immunopositive nerve fibers in the hip joint of patients with painful osteoarthritis and of patients with painless failed total hip arthroplasties","volume":"11","author":"Saxler","year":"2007","journal-title":"Eur. J. Pain"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1097\/00003086-200007000-00024","article-title":"Distribution of Neuropeptides in Synovium of the Knee with Osteoarthritis","volume":"376","author":"Saito","year":"2000","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.neulet.2005.06.044","article-title":"Regulation of calcitonin gene-related peptide and TRPV1 in a rat model of osteoarthritis","volume":"388","author":"Fernihough","year":"2005","journal-title":"Neurosci. Lett."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3677","DOI":"10.1002\/art.27713","article-title":"Phenotypic alterations of neurons that innervate osteoarthritic joints in rats","volume":"62","author":"Sarkander","year":"2010","journal-title":"Arthritis Rheum."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1016\/j.pain.2013.01.002","article-title":"The CGRP receptor antagonist BIBN4096BS peripherally alleviates inflammatory pain in rats","volume":"154","author":"Hirsch","year":"2013","journal-title":"Pain"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/S8756-3282(01)00494-X","article-title":"Effects of calcitonin, amylin, and calcitonin gene-related peptide on osteoclast development","volume":"29","author":"Cornish","year":"2001","journal-title":"Bone"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"15354","DOI":"10.1038\/s41598-023-42673-2","article-title":"Feasibility of administration of calcitonin gene-related peptide receptor antagonist on attenuation of pain and progression in osteoarthritis","volume":"13","author":"Nekomoto","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Sun, L., Wang, G., He, M., Mei, Z., Zhang, F., and Liu, P. (2020). Effect and mechanism of the CACNA2D1-CGRP pathway in osteoarthritis-induced ongoing pain. Biomed. Pharmacother., 129.","DOI":"10.1016\/j.biopha.2020.110374"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/S0304-3959(00)00242-6","article-title":"Alleviation of mechanical and thermal allodynia by CGRP(8-37) in a rodent model of chronic central pain","volume":"86","author":"Bennett","year":"2000","journal-title":"Pain"},{"key":"ref_10","first-page":"E331","article-title":"Calcitonin gene-related peptide receptor antagonist human CGRP-(8-37)","volume":"256","author":"Chiba","year":"1989","journal-title":"Am. J. Physiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1002\/ana.21537","article-title":"Medullary pain facilitating neurons mediate allodynia in headache-related pain","volume":"65","author":"Edelmayer","year":"2009","journal-title":"Ann. Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1021\/jm050613s","article-title":"Identification of the key residue of calcitonin gene related peptide (CGRP) 27-37 to obtain antagonists with picomolar affinity at the CGRP receptor","volume":"49","author":"Lang","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"101771","DOI":"10.1016\/j.jchemneu.2020.101771","article-title":"The role of CGRP receptor antagonist (CGRP8\u201337) and Endomorphin-1 combination therapy on neuropathic pain alleviation and expression of Sigma-1 receptors and antioxidants in rats","volume":"106","author":"Janzadeh","year":"2020","journal-title":"J. Chem. Neuroanat."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1002\/immu.200390026","article-title":"Intramuscular transfer of naked calcitonin gene-related peptide gene prevents autoimmune diabetes induced by multiple low-dose streptozotocin in C57BL mice","volume":"33","author":"Sun","year":"2003","journal-title":"Eur. J. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2188","DOI":"10.1002\/art.38656","article-title":"Peripheral calcitonin gene-related peptide receptor activation and mechanical sensitization of the joint in rat models of osteoarthritis pain","volume":"66","author":"Bullock","year":"2014","journal-title":"Arthritis Rheumatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1186\/s10194-022-01531-8","article-title":"CGRP-dependent sensitization of PKC-delta positive neurons in central amygdala mediates chronic migraine","volume":"23","author":"Chou","year":"2022","journal-title":"J. Headache. Pain"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"115428","DOI":"10.1016\/j.taap.2021.115428","article-title":"Role of calcitonin gene-related peptide in pain regulation in the parabrachial nucleus of naive rats and rats with neuropathic pain","volume":"414","author":"Wang","year":"2021","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"114351","DOI":"10.1016\/j.bbr.2023.114351","article-title":"Calcitonin gene-related peptide and its receptor plays important role in nociceptive regulation in the arcuate nucleus of hypothalamus of rats with inflammatory pain","volume":"443","author":"Luo","year":"2023","journal-title":"Behav. Brain Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"809118","DOI":"10.3389\/fmed.2021.809118","article-title":"Gene Therapy Advances: A Meta-Analysis of AAV Usage in Clinical Settings","volume":"8","author":"Au","year":"2022","journal-title":"Front. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1002\/jor.20498","article-title":"Preponderance of sensory versus sympathetic nerve fibers and increased cellularity in the infrapatellar fat pad in anterior knee pain patients after primary arthroplasty","volume":"26","author":"Lehner","year":"2008","journal-title":"J. Orthop. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1543","DOI":"10.4049\/jimmunol.1601751","article-title":"Role of Substance P Neuropeptide in Inflammation, Wound Healing, and Tissue Homeostasis","volume":"199","author":"Suvas","year":"2017","journal-title":"J. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4249","DOI":"10.1007\/s00018-016-2293-z","article-title":"Neuropeptide substance P and the immune response","volume":"73","author":"Mashaghi","year":"2016","journal-title":"Cell. Mol. Life Sci. CMLS"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1189\/jlb.1AB0416-188RR","article-title":"Substance P\u2013mediated chemokine production promotes monocyte migration","volume":"101","author":"Spitsin","year":"2017","journal-title":"J. Leukoc. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1128\/cdli.1.3.330-335.1994","article-title":"Characterization of substance P binding to human monocytes\/macrophages","volume":"1","author":"Lucey","year":"1994","journal-title":"Clin. Diagn. Lab. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"9417","DOI":"10.1038\/s41598-017-09639-7","article-title":"A neuropeptide, Substance-P, directly induces tissue-repairing M2 like macrophages by activating the PI3K\/Akt\/mTOR pathway even in the presence of IFN\u03b3","volume":"7","author":"Lim","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1002\/stem.592","article-title":"Concise review: Neutral endopeptidase (CD10): A multifaceted environment actor in stem cells, physiological mechanisms, and cancer","volume":"29","author":"Besancon","year":"2011","journal-title":"Stem Cells"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1016\/j.jcyt.2013.02.006","article-title":"Stromal cells from the adipose tissue-derived stromal vascular fraction and culture expanded adipose tissue-derived stromal\/stem cells: A joint statement of the International Federation for Adipose Therapeutics and Science (IFATS) and the International Society for Cellular Therapy (ISCT)","volume":"15","author":"Bourin","year":"2013","journal-title":"Cytotherapy"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"10864","DOI":"10.1038\/s41598-019-47391-2","article-title":"Infrapatellar fat pad-derived MSC response to inflammation and fibrosis induces an immunomodulatory phenotype involving CD10-mediated Substance P degradation","volume":"9","author":"Kouroupis","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2013","DOI":"10.1177\/0363546520917699","article-title":"CD10\/neprilysin enrichment in infrapatellar fat pad-derived MSC under regulatory-compliant conditions: Implications for efficient synovitis and fat pad fibrosis reversal","volume":"40","author":"Kouroupis","year":"2020","journal-title":"Am. J. Sports Med."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Kouroupis, D., Kaplan, L.D., Huard, J., and Best, T.M. (2023). CD10-Bound Human Mesenchymal Stem\/Stromal Cell-Derived Small Extracellular Vesicles Possess Immunomodulatory Cargo and Maintain Cartilage Homeostasis under Inflammatory Conditions. Cells, 12.","DOI":"10.20944\/preprints202305.1465.v1"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4142","DOI":"10.3390\/ijms15034142","article-title":"Exosomes derived from mesenchymal stem cells","volume":"15","author":"Yu","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1016\/j.jcyt.2017.01.001","article-title":"A Good Manufacturing Practice\u2013grade standard protocol for exclusively human mesenchymal stromal cell\u2013derived extracellular vesicles","volume":"19","author":"Pachler","year":"2017","journal-title":"Cytotherapy"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"19861","DOI":"10.3402\/jev.v2i0.19861","article-title":"How pure are your vesicles?","volume":"2","author":"Webber","year":"2013","journal-title":"J. Extracell. Vesicles"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3609","DOI":"10.1038\/s41598-022-07569-7","article-title":"Human infrapatellar fat pad mesenchymal stem cells show immunomodulatory exosomal signatures","volume":"12","author":"Kouroupis","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"D127","DOI":"10.1093\/nar\/gkz757","article-title":"miRDB: An online database for prediction of functional microRNA targets","volume":"48","author":"Chen","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1002\/cne.22027","article-title":"Combined extrinsic and intrinsic manipulations exert complementary neuronal enrichment in embryonic rat neural precursor cultures: An in vitro and in vivo analysis","volume":"515","author":"Furmanski","year":"2009","journal-title":"J. Comp. Neurol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1002\/(SICI)1097-0185(199701)247:1<109::AID-AR13>3.0.CO;2-T","article-title":"Microtopography of the autonomic nerves in the rat knee: A fluorescence microscopic study","volume":"247","author":"Schwab","year":"1997","journal-title":"Anat. Rec. Off. Publ. Am. Assoc. Anat."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.stemcr.2014.01.002","article-title":"Identification of specific cell-surface markers of adipose-derived stem cells from subcutaneous and visceral fat depots","volume":"2","author":"Ong","year":"2014","journal-title":"Stem Cell Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1002\/stem.1681","article-title":"Concise Review: The Surface Markers and Identity of Human Mesenchymal Stem Cells","volume":"32","author":"Lv","year":"2014","journal-title":"Stem Cells"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1007\/s00403-010-1093-9","article-title":"CD10-bearing fibroblasts may inhibit skin inflammation by down-modulating substance P","volume":"303","author":"Xie","year":"2011","journal-title":"Arch. Dermatol. Res."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Le\u00f1ero, C., Kaplan, L.D., Best, T.M., and Kouroupis, D. (2022). CD146+ Endometrial-Derived Mesenchymal Stem\/Stromal Cell Subpopulation Possesses Exosomal Secretomes with Strong Immunomodulatory miRNA Attributes. Cells, 11.","DOI":"10.3390\/cells11244002"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"bqz016","DOI":"10.1210\/endocr\/bqz016","article-title":"Inhibition of FGFR Signaling Partially Rescues Osteoarthritis in Mice Overexpressing High Molecular Weight FGF2 Isoforms","volume":"161","author":"Xiao","year":"2020","journal-title":"Endocrinology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"65","DOI":"10.11005\/jbm.2018.25.2.65","article-title":"Differential Role of Transforming Growth Factor-beta in an Osteoarthritic or a Healthy Joint","volume":"25","year":"2018","journal-title":"J. Bone Metab."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1007\/s11926-017-0679-z","article-title":"Wnt\/beta-catenin Signaling in Osteoarthritis and in Other Forms of Arthritis","volume":"19","author":"Zhou","year":"2017","journal-title":"Curr. Rheumatol. Rep."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/j.tcb.2004.05.011","article-title":"Rita Levi-Montalcini: The discovery of nerve growth factor and modern neurobiology","volume":"14","author":"Aloe","year":"2004","journal-title":"Trends Cell Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"R16","DOI":"10.1186\/ar4443","article-title":"Induction of nerve growth factor expression and release by mechanical and inflammatory stimuli in chondrocytes: Possible involvement in osteoarthritis pain","volume":"16","author":"Pecchi","year":"2014","journal-title":"Arthritis Res. Ther."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Barreto, G., Manninen, M., and Eklund, K.K. (2020). Osteoarthritis and Toll-Like Receptors: When Innate Immunity Meets Chondrocyte Apoptosis. Biology, 9.","DOI":"10.3390\/biology9040065"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"93","DOI":"10.22203\/eCM.v013a10","article-title":"Adeno-associated viral vector transduction of human mesenchymal stem cells","volume":"13","author":"Stender","year":"2007","journal-title":"Eur. Cell Mater."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1502","DOI":"10.1002\/jcp.27014","article-title":"Exosome-encapsulated miR-6089 regulates inflammatory response via targeting TLR4","volume":"234","author":"Xu","year":"2019","journal-title":"J. Cell. Physiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1038\/s41419-018-0805-5","article-title":"MicroRNA-21 prevents excessive inflammation and cardiac dysfunction after myocardial infarction through targeting KBTBD7","volume":"9","author":"Yang","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1007\/s11626-021-00606-1","article-title":"miR-23a-3p regulates the inflammatory response and fibrosis in diabetic kidney disease by targeting early growth response 1","volume":"57","author":"Sheng","year":"2021","journal-title":"Vitr. Cell. Dev. Biol. Anim."},{"key":"ref_52","first-page":"7172583","article-title":"miR-99a-5p: A Potential New Therapy for Atherosclerosis by Targeting mTOR and Then Inhibiting NLRP3 Inflammasome Activation and Promoting Macrophage Autophagy","volume":"2022","author":"Wang","year":"2022","journal-title":"Dis. Markers"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1165\/rcmb.2020-0112OC","article-title":"MicroRNA-574-5p Attenuates Acute Respiratory Distress Syndrome by Targeting HMGB1","volume":"64","author":"He","year":"2021","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"12029","DOI":"10.1002\/jcp.27864","article-title":"microRNA-107 protects against inflammation and endoplasmic reticulum stress of vascular endothelial cells via KRT1-dependent Notch signaling pathway in a mouse model of coronary atherosclerosis","volume":"234","author":"Gao","year":"2019","journal-title":"J. Cell. Physiol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"653344","DOI":"10.3389\/fimmu.2021.653344","article-title":"MicroLet-7b Regulates Neutrophil Function and Dampens Neutrophilic Inflammation by Suppressing the Canonical TLR4\/NF-kappaB Pathway","volume":"12","author":"Chen","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Guz, M., Jeleniewicz, W., and Cybulski, M. (2022). An Insight into miR-1290: An Oncogenic miRNA with Diagnostic Potential. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031234"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"220","DOI":"10.3389\/fnmol.2019.00220","article-title":"TIMP-1 Attenuates the Development of Inflammatory Pain Through MMP-Dependent and Receptor-Mediated Cell Signaling Mechanisms","volume":"12","author":"Knight","year":"2019","journal-title":"Front. Mol. Neurosci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1186\/1742-2094-11-116","article-title":"The anti-inflammatory role of tissue inhibitor of metalloproteinase-2 in lipopolysaccharide-stimulated microglia","volume":"11","author":"Lee","year":"2014","journal-title":"J. Neuroinflammation"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/j.bbrc.2012.05.132","article-title":"TIMP2 deficient mice develop accelerated osteoarthritis via promotion of angiogenesis upon destabilization of the medial meniscus","volume":"423","author":"Mi","year":"2012","journal-title":"Biochem. Bioph. Res. Commun."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.cyto.2016.12.001","article-title":"Relationship of inflammatory profile of elderly patients serum and senescence-associated secretory phenotype with human breast cancer cells proliferation: Role of IL6\/IL8 ratio","volume":"91","year":"2017","journal-title":"Cytokine"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1002\/JLB.2MR0220-549R","article-title":"ICAM-1: A master regulator of cellular responses in inflammation, injury resolution, and tumorigenesis","volume":"108","author":"Bui","year":"2020","journal-title":"J. Leukoc. Biol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"3858","DOI":"10.4049\/jimmunol.1302821","article-title":"CCL2 shapes macrophage polarization by GM-CSF and M-CSF: Identification of CCL2\/CCR2-dependent gene expression profile","volume":"192","author":"Nieto","year":"2014","journal-title":"J. Immunol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2504","DOI":"10.1016\/j.celrep.2018.02.013","article-title":"Potency Analysis of Mesenchymal Stromal Cells Using a Combinatorial Assay Matrix Approach","volume":"22","author":"Chinnadurai","year":"2018","journal-title":"Cell Rep."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"5771","DOI":"10.4049\/jimmunol.180.9.5771","article-title":"IL-10: The Master Regulator of Immunity to Infection","volume":"180","author":"Couper","year":"2008","journal-title":"J. Immunol."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Tonomura, H., Nagae, M., Takatori, R., Ishibashi, H., Itsuji, T., and Takahashi, K. (2020). The Potential Role of Hepatocyte Growth Factor in Degenerative Disorders of the Synovial Joint and Spine. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21228717"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"eabb3946","DOI":"10.1126\/scitranslmed.abb3946","article-title":"Targeting cartilage EGFR pathway for osteoarthritis treatment","volume":"13","author":"Wei","year":"2021","journal-title":"Sci. Transl. Med."},{"key":"ref_67","first-page":"1667","article-title":"VEGF secreted by mesenchymal stem cells mediates the differentiation of endothelial progenitor cells into endothelial cells via paracrine mechanisms","volume":"17","author":"Ge","year":"2018","journal-title":"Mol. Med. Rep."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1186\/s13075-021-02662-0","article-title":"Insulin-like growth factor-1 in articular cartilage repair for osteoarthritis treatment","volume":"23","author":"Wen","year":"2021","journal-title":"Arthritis Res. Ther."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1038\/s41584-020-0469-2","article-title":"Fibroblast growth factor signalling in osteoarthritis and cartilage repair","volume":"16","author":"Xie","year":"2020","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1159\/000252803","article-title":"Expression of the inhibitory CD200 receptor is associated with alternative macrophage activation","volume":"2","author":"Koning","year":"2010","journal-title":"J. Innate Immun."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Rocher, C., and Singla, D.K. (2013). SMAD-PI3K-Akt-mTOR pathway mediates BMP-7 polarization of monocytes into M2 macrophages. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0084009"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1016\/j.immuni.2016.09.016","article-title":"Metabolic Reprogramming Mediated by the mTORC2-IRF4 Signaling Axis Is Essential for Macrophage Alternative Activation","volume":"45","author":"Huang","year":"2016","journal-title":"Immunity"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1177\/1753425916668243","article-title":"Regulation of the IL-10-driven macrophage phenotype under incoherent stimuli","volume":"22","author":"Chuang","year":"2016","journal-title":"Innate Immun."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"632912","DOI":"10.3389\/fphar.2021.632912","article-title":"Il12a Deletion Aggravates Sepsis-Induced Cardiac Dysfunction by Regulating Macrophage Polarization","volume":"12","author":"Wang","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Newton, K., and Dixit, V.M. (2012). Signaling in innate immunity and inflammation. Cold Spring Harb. Perspect. Biol., 4.","DOI":"10.1101\/cshperspect.a006049"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1021\/np200666t","article-title":"Anti-inflammatory Mechanism of 15,16-Epoxy-3\u03b1-hydroxylabda-8,13(16),14-trien-7-one via Inhibition of LPS-Induced Multicellular Signaling Pathways","volume":"75","author":"Khan","year":"2012","journal-title":"J. Nat. Prod."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.brainresrev.2008.12.011","article-title":"MAP kinase and pain","volume":"60","author":"Ji","year":"2009","journal-title":"Brain. Res. Rev."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.neulet.2008.03.017","article-title":"Activation of JNK pathway in persistent pain","volume":"437","author":"Gao","year":"2008","journal-title":"Neurosci. Lett."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"9491","DOI":"10.1523\/JNEUROSCI.4404-14.2015","article-title":"ERK2 Alone Drives Inflammatory Pain But Cooperates with ERK1 in Sensory Neuron Survival","volume":"35","author":"Alter","year":"2015","journal-title":"J. Neurosci."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/6\/484\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:11:29Z","timestamp":1760105489000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/6\/484"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,10]]},"references-count":79,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2024,3]]}},"alternative-id":["cells13060484"],"URL":"https:\/\/doi.org\/10.3390\/cells13060484","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,10]]}}}