{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T15:24:57Z","timestamp":1780068297290,"version":"3.54.0"},"reference-count":47,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,5,26]],"date-time":"2023-05-26T00:00:00Z","timestamp":1685059200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"the National Institute of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["R01AR070821"],"award-info":[{"award-number":["R01AR070821"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"the National Institute of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["P30 AR072580"],"award-info":[{"award-number":["P30 AR072580"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"the National Institute of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["872648"],"award-info":[{"award-number":["872648"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"\u201cAsociaci\u00f3n de Amigos de la Universidad de Navarra\u201d","award":["R01AR070821"],"award-info":[{"award-number":["R01AR070821"]}]},{"name":"\u201cAsociaci\u00f3n de Amigos de la Universidad de Navarra\u201d","award":["P30 AR072580"],"award-info":[{"award-number":["P30 AR072580"]}]},{"name":"\u201cAsociaci\u00f3n de Amigos de la Universidad de Navarra\u201d","award":["872648"],"award-info":[{"award-number":["872648"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>In osteoarthritis (OA), bone changes are radiological hallmarks and are considered important for disease progression. The C-C chemokine receptor-2 (CCR2) has been shown to play an important role in bone physiology. In this study, we investigated whether Ccr2 osteoblast-specific inactivation at different times during post-traumatic OA (PTOA) progression improves joint structures, bone parameters, and pain. We used a tamoxifen-inducible Ccr2 inactivation in Collagen1\u03b1-expressing cells to obtain osteoblasts lacking Ccr2 (CCR2-Col1\u03b1KO). We stimulated PTOA changes in CCR2-Col1\u03b1KO and CCR2+\/+ mice using the destabilization of the meniscus model (DMM), inducing recombination before or after DMM (early- vs. late-inactivation). Joint damage was evaluated at two, four, eight, and twelve weeks post-DMM using multiple scores: articular-cartilage structure (ACS), Safranin-O, histomorphometry, osteophyte size\/maturity, subchondral bone thickness and synovial hyperplasia. Spontaneous and evoked pain were assessed for up to 20 weeks. We found that early osteoblast-Ccr2 inactivation delayed articular cartilage damage and matrix degeneration compared to CCR2+\/+, as well as DMM-induced bone thickness. Osteophyte formation and maturation were only minimally affected. Late Collagen1\u03b1-Ccr2 deletion led to less evident improvements. Osteoblast-Ccr2 deletion also improved static measures of pain, while evoked pain did not change. Our study demonstrates that Ccr2 expression in osteoblasts contributes to PTOA disease progression and pain by affecting both cartilage and bone tissues.<\/jats:p>","DOI":"10.3390\/biom13060891","type":"journal-article","created":{"date-parts":[[2023,5,27]],"date-time":"2023-05-27T16:19:37Z","timestamp":1685204377000},"page":"891","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["CC-Chemokine Receptor-2 Expression in Osteoblasts Contributes to Cartilage and Bone Damage during Post-Traumatic Osteoarthritis"],"prefix":"10.3390","volume":"13","author":[{"given":"Helen","family":"Willcockson","sequence":"first","affiliation":[{"name":"Division of Rheumatology, Allergy and Immunology, University of North Carolina at Chapel Hill, 3300 Thurston Bldg, Campus Box 7280, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huseyin","family":"Ozkan","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Allergy and Immunology, University of North Carolina at Chapel Hill, 3300 Thurston Bldg, Campus Box 7280, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9","family":"Vald\u00e9s-Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Program of Regenerative Medicine, Center for Applied Medical Research (CIMA), Universidad de Navarra, 31008 Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liubov","family":"Arbeeva","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Allergy and Immunology, University of North Carolina at Chapel Hill, 3300 Thurston Bldg, Campus Box 7280, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esra","family":"Mucahit","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Allergy and Immunology, University of North Carolina at Chapel Hill, 3300 Thurston Bldg, Campus Box 7280, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Layla","family":"Musawwir","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Allergy and Immunology, University of North Carolina at Chapel Hill, 3300 Thurston Bldg, Campus Box 7280, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lola B.","family":"Hooper","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Allergy and Immunology, University of North Carolina at Chapel Hill, 3300 Thurston Bldg, Campus Box 7280, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4817-5232","authenticated-orcid":false,"given":"Froil\u00e1n","family":"Granero-Molt\u00f3","sequence":"additional","affiliation":[{"name":"Program of Regenerative Medicine, Center for Applied Medical Research (CIMA), Universidad de Navarra, 31008 Pamplona, Spain"},{"name":"Department of Orthopedic Surgery and Traumatology, Cl\u00ednica Universidad de Navarra, 31008 Pamplona, Spain"},{"name":"Instituto de Investigacion Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6115-8790","authenticated-orcid":false,"given":"Felipe","family":"Pr\u00f3sper","sequence":"additional","affiliation":[{"name":"Program of Regenerative Medicine, Center for Applied Medical Research (CIMA), Universidad de Navarra, 31008 Pamplona, Spain"},{"name":"Instituto de Investigacion Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain"},{"name":"Department of Hematology and Cell Therapy and CCUN, Cl\u00ednica Universidad de Navarra, 31008 Pamplona, Spain"},{"name":"CIBERONC, 28029 Madrid, Spain"},{"name":"Program of Hemato-Oncology, Center for Applied Medical Research (CIMA), Universidad de Navarra, 31008 Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0156-847X","authenticated-orcid":false,"given":"Lara","family":"Longobardi","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Allergy and Immunology, University of North Carolina at Chapel Hill, 3300 Thurston Bldg, Campus Box 7280, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/nrrheum.2010.196","article-title":"Role of proinflammatory cytokines in the pathophysiology of osteoarthritis","volume":"7","author":"Kapoor","year":"2011","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1136\/annrheumdis-2016-210426","article-title":"CCL2\/CCR2, but not CCL5\/CCR5, mediates monocyte recruitment, inflammation and cartilage destruction in osteoarthritis","volume":"76","author":"Raghu","year":"2017","journal-title":"Ann. Rheum. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2691","DOI":"10.1002\/art.39255","article-title":"Reduction in disease progression by inhibition of transforming growth factor alpha-CCL2 signaling in experimental posttraumatic osteoarthritis","volume":"67","author":"Appleton","year":"2015","journal-title":"Arthritis Rheumatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1177\/0004563214545117","article-title":"Serum and synovial fluid chemokine ligand 2\/monocyte chemoattractant protein 1 concentrations correlates with symptomatic severity in patients with knee osteoarthritis","volume":"52","author":"Li","year":"2015","journal-title":"Ann. Clin. Biochem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1016\/j.joca.2018.04.012","article-title":"Associations between the chemokine biomarker CCL2 and knee osteoarthritis outcomes: The Johnston County Osteoarthritis Project","volume":"26","author":"Longobardi","year":"2018","journal-title":"Osteoarthr. Cartil."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1016\/j.joca.2016.11.004","article-title":"Role of the C-C chemokine receptor-2 in a murine model of injury-induced osteoarthritis","volume":"25","author":"Longobardi","year":"2017","journal-title":"Osteoarthr. Cartil."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"20602","DOI":"10.1073\/pnas.1209294110","article-title":"CCR2 chemokine receptor signaling mediates pain in experimental osteoarthritis","volume":"109","author":"Miller","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/j.joca.2016.10.008","article-title":"CCL2 and CCR2 regulate pain-related behaviour and early gene expression in post-traumatic murine osteoarthritis but contribute little to chondropathy","volume":"25","author":"Chanalaris","year":"2017","journal-title":"Osteoarthr. Cartil."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1007\/s13346-022-01235-1","article-title":"Sustained inhibition of CC-chemokine receptor-2 via intraarticular deposition of polymeric microplates in post-traumatic osteoarthritis","volume":"13","author":"Ozkan","year":"2022","journal-title":"Drug Deliv. Transl. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1616","DOI":"10.1016\/j.joca.2022.08.015","article-title":"Early Ablation of Ccr2 in Aggrecan-expressing cells Following Knee Injury Ameliorates Joint Damage and Pain during Post-traumatic Osteoarthritis","volume":"30","author":"Willcockson","year":"2022","journal-title":"Osteoarthr. Cartil."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1038\/nm.1945","article-title":"Estrogen-dependent and C-C chemokine receptor-2-dependent pathways determine osteoclast behavior in osteoporosis","volume":"15","author":"Binder","year":"2009","journal-title":"Nat. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1242\/dmm.003186","article-title":"Multiple roles for CCR2 during fracture healing","volume":"3","author":"Xing","year":"2010","journal-title":"Dis. Model. Mech."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1172\/JCI200420126","article-title":"Experimental arthritis in CC chemokine receptor 2-null mice closely mimics severe human rheumatoid arthritis","volume":"113","author":"Quinones","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.ajodo.2011.07.019","article-title":"Role of CCR2 in orthodontic tooth movement","volume":"141","author":"Taddei","year":"2012","journal-title":"Am. J. Orthod. Dentofac. Orthop."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"von Luettichau, I., Segerer, S., Wechselberger, A., Notohamiprodjo, M., Nathrath, M., Kremer, M., Henger, A., Djafarzadeh, R., Burdach, S., and Huss, R. (2008). A complex pattern of chemokine receptor expression is seen in osteosarcoma. BMC Cancer, 8.","DOI":"10.1186\/1471-2407-8-23"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"R100","DOI":"10.1186\/ar2301","article-title":"Microarray gene expression profiling of osteoarthritic bone suggests altered bone remodelling, WNT and transforming growth factor-beta\/bone morphogenic protein signalling","volume":"9","author":"Hopwood","year":"2007","journal-title":"Arthritis Res. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1875","DOI":"10.1016\/S0002-9440(10)63240-3","article-title":"Transgenic mice expressing a ligand-inducible cre recombinase in osteoblasts and odontoblasts: A new tool to examine physiology and disease of postnatal bone and tooth","volume":"165","author":"Kim","year":"2004","journal-title":"Am. J. Pathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1182\/blood-2012-01-403386","article-title":"CCR2 recruits an inflammatory macrophage subpopulation critical for angiogenesis in tissue repair","volume":"120","author":"Willenborg","year":"2012","journal-title":"Blood"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1038\/nature03369","article-title":"Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis","volume":"434","author":"Glasson","year":"2005","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2547","DOI":"10.1002\/art.20558","article-title":"Characterization of and osteoarthritis susceptibility in ADAMTS-4-knockout mice","volume":"50","author":"Glasson","year":"2004","journal-title":"Arthritis Rheum."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1016\/j.joca.2007.03.006","article-title":"The surgical destabilization of the medial meniscus (DMM) model of osteoarthritis in the 129\/SvEv mouse","volume":"15","author":"Glasson","year":"2007","journal-title":"Osteoarthr. Cartil."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1016\/j.joca.2006.11.005","article-title":"Osteoarthritis severity is sex dependent in a surgical mouse model","volume":"15","author":"Ma","year":"2007","journal-title":"Osteoarthr. Cartil."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1016\/S1063-4584(03)00163-8","article-title":"Weight bearing as a measure of disease progression and efficacy of anti-inflammatory compounds in a model of monosodium iodoacetate-induced osteoarthritis","volume":"11","author":"Bove","year":"2003","journal-title":"Osteoarthr. Cartil.\/OARS Osteoarthr. Res. Soc."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0165-0270(94)90144-9","article-title":"Quantitative assessment of tactile allodynia in the rat paw","volume":"53","author":"Chaplan","year":"1994","journal-title":"J. Neurosci. Methods"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1177\/1947603511402665","article-title":"A Comprehensive Histological Assessment of Osteoarthritis Lesions in Mice","volume":"2","author":"McNulty","year":"2011","journal-title":"Cartilage"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"10077","DOI":"10.1038\/s41598-020-66979-7","article-title":"Histological scoring system for subchondral bone changes in murine models of joint aging and osteoarthritis","volume":"10","author":"Nagira","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3723","DOI":"10.1002\/art.25002","article-title":"Matrix metalloproteinase 13-deficient mice are resistant to osteoarthritic cartilage erosion but not chondrocyte hypertrophy or osteophyte development","volume":"60","author":"Little","year":"2009","journal-title":"Arthritis Rheum."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1002\/art.39844","article-title":"Reduced Osteoarthritis Severity in Aged Mice With Deletion of Macrophage Migration Inhibitory Factor","volume":"69","author":"Rowe","year":"2017","journal-title":"Arthritis Rheumatol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1038\/nrrheum.2012.130","article-title":"Bone remodelling in osteoarthritis","volume":"8","author":"Burr","year":"2012","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1186\/s13075-022-02905-8","article-title":"Osteophytes mediate the associations between cartilage morphology and changes in knee symptoms in patients with knee osteoarthritis","volume":"24","author":"Fan","year":"2022","journal-title":"Arthritis Res. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1089\/gtmb.2011.0216","article-title":"MCP-1 and CCR2 gene variants and the risk for osteoporosis and osteopenia","volume":"16","author":"Eraltan","year":"2012","journal-title":"Genet. Test. Mol. Biomark."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"7211","DOI":"10.1002\/jcp.30375","article-title":"The molecular structure and role of CCL2 (MCP-1) and C-C chemokine receptor CCR2 in skeletal biology and diseases","volume":"236","author":"Zhu","year":"2021","journal-title":"J. Cell. Physiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1186\/ar4405","article-title":"Subchondral bone in osteoarthritis: Insight into risk factors and microstructural changes","volume":"15","author":"Li","year":"2013","journal-title":"Arthritis Res. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1007\/s00167-010-1054-z","article-title":"The basic science of the subchondral bone","volume":"18","author":"Madry","year":"2010","journal-title":"Knee Surg. Sport. Traumatol. Arthrosc."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.bcp.2011.09.018","article-title":"Subchondral bone as a key target for osteoarthritis treatment","volume":"83","author":"Castaneda","year":"2012","journal-title":"Biochem. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2855","DOI":"10.1038\/s41598-018-21184-5","article-title":"Early Changes of Articular Cartilage and Subchondral Bone in The DMM Mouse Model of Osteoarthritis","volume":"8","author":"Fang","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1038\/nrrheum.2013.138","article-title":"Towards a mechanism-based approach to pain management in osteoarthritis","volume":"9","author":"Malfait","year":"2013","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1016\/S0140-6736(14)60802-3","article-title":"Osteoarthritis","volume":"386","author":"Palmer","year":"2015","journal-title":"Lancet"},{"key":"ref_39","first-page":"646","article-title":"Burden of major musculoskeletal conditions","volume":"81","author":"Woolf","year":"2003","journal-title":"Bull. World Health Organ."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1302\/2046-3758.117.BJR-2021-0355.R1","article-title":"Peripheral nerves in the tibial subchondral bone: The role of pain and homeostasis in osteoarthritis","volume":"11","author":"Sun","year":"2022","journal-title":"Bone Jt. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.1172\/JCI121561","article-title":"Subchondral bone osteoclasts induce sensory innervation and osteoarthritis pain","volume":"129","author":"Zhu","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1136\/ard.2006.063354","article-title":"Neurovascular invasion at the osteochondral junction and in osteophytes in osteoarthritis","volume":"66","author":"Suri","year":"2007","journal-title":"Ann. Rheum. Dis."},{"key":"ref_43","first-page":"843 e841-814","article-title":"Brain activity for chronic knee osteoarthritis: Dissociating evoked pain from spontaneous pain","volume":"15","author":"Parks","year":"2011","journal-title":"Eur. J. Pain"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"7947","DOI":"10.1073\/pnas.1331358100","article-title":"Impaired neuropathic pain responses in mice lacking the chemokine receptor CCR2","volume":"100","author":"Abbadie","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1136\/ard.2006.052548","article-title":"Symptoms and radiographic osteoarthritis: Not as discordant as they are made out to be?","volume":"66","author":"Duncan","year":"2007","journal-title":"Ann. Rheum. Dis."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"b2844","DOI":"10.1136\/bmj.b2844","article-title":"Association between radiographic features of knee osteoarthritis and pain: Results from two cohort studies","volume":"339","author":"Neogi","year":"2009","journal-title":"BMJ"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1016\/j.joca.2017.01.019","article-title":"Can we target CCR2 to treat osteoarthritis? The trick is in the timing!","volume":"25","author":"Miller","year":"2017","journal-title":"Osteoarthr. Cartil."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/6\/891\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:42:58Z","timestamp":1760125378000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/6\/891"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,26]]},"references-count":47,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,6]]}},"alternative-id":["biom13060891"],"URL":"https:\/\/doi.org\/10.3390\/biom13060891","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,26]]}}}