Inflammatory cytokines and mechanical injury induce post-traumatic osteoarthritis-like changes in a human cartilage-bone-synovium microphysiological system
Abstract Background Traumatic knee injuries in humans trigger an immediate increase in synovial fluid levels of inflammatory cytokines that accompany impact damage to joint tissues. We developed a human in vitro cartilage-bone-synovium (CBS) coculture model to study the role of mechanical injury and...
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| Format: | Article |
| Language: | English |
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BMC
2022-08-01
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| Series: | Arthritis Research & Therapy |
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| Online Access: | https://doi.org/10.1186/s13075-022-02881-z |
| _version_ | 1811340154252558336 |
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| author | Garima Dwivedi Lisa Flaman Begum Alaybeyoglu André Struglics Eliot H. Frank Susan Chubinskya Stephen B. Trippel Vicki Rosen Murat Cirit Alan J. Grodzinsky |
| author_facet | Garima Dwivedi Lisa Flaman Begum Alaybeyoglu André Struglics Eliot H. Frank Susan Chubinskya Stephen B. Trippel Vicki Rosen Murat Cirit Alan J. Grodzinsky |
| author_sort | Garima Dwivedi |
| collection | DOAJ |
| description | Abstract Background Traumatic knee injuries in humans trigger an immediate increase in synovial fluid levels of inflammatory cytokines that accompany impact damage to joint tissues. We developed a human in vitro cartilage-bone-synovium (CBS) coculture model to study the role of mechanical injury and inflammation in the initiation of post-traumatic osteoarthritis (PTOA)-like disease. Methods Osteochondral plugs (cartilage-bone, CB) along with joint capsule synovium explants (S) were harvested from 25 cadaveric distal femurs from 16 human donors (Collin’s grade 0–2, 23–83years). Two-week monocultures (cartilage (C), bone (B), synovium (S)) and cocultures (CB, CBS) were established. A PTOA-like disease group was initiated via coculture of synovium explants with mechanically impacted osteochondral plugs (CBS+INJ, peak stress 5MPa) with non-impacted CB as controls. Disease-like progression was assessed through analyses of changes in cell viability, inflammatory cytokines released to media (10-plex ELISA), tissue matrix degradation, and metabolomics profile. Results Immediate increases in concentrations of a panel of inflammatory cytokines occurred in CBS+INJ and CBS cocultures and cultures with S alone (IL-1, IL-6, IL-8, and TNF-α among others). CBS+INJ and CBS also showed increased chondrocyte death compared to uninjured CB. The release of sulfated glycosaminoglycans (sGAG) and associated ARGS-aggrecan neoepitope fragments to the medium was significantly increased in CBS and CBS+INJ groups. Distinct metabolomics profiles were observed for C, B, and S monocultures, and metabolites related to inflammatory response in CBS versus CB (e.g., kynurenine, 1-methylnicotinamide, and hypoxanthine) were identified. Conclusion CBS and CBS+INJ models showed distinct cellular, inflammatory, and matrix-related alterations relevant to PTOA-like initiation/progression. The use of human knee tissues from donors that had no prior history of OA disease suggests the relevance of this model in highlighting the role of injury and inflammation in earliest stages of PTOA progression. |
| first_indexed | 2024-04-13T18:37:55Z |
| format | Article |
| id | doaj.art-522239d893064200834c5e4152161f6f |
| institution | Directory Open Access Journal |
| issn | 1478-6362 |
| language | English |
| last_indexed | 2024-04-13T18:37:55Z |
| publishDate | 2022-08-01 |
| publisher | BMC |
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| series | Arthritis Research & Therapy |
| spelling | doaj.art-522239d893064200834c5e4152161f6f2022-12-22T02:34:49ZengBMCArthritis Research & Therapy1478-63622022-08-0124111810.1186/s13075-022-02881-zInflammatory cytokines and mechanical injury induce post-traumatic osteoarthritis-like changes in a human cartilage-bone-synovium microphysiological systemGarima Dwivedi0Lisa Flaman1Begum Alaybeyoglu2André Struglics3Eliot H. Frank4Susan Chubinskya5Stephen B. Trippel6Vicki Rosen7Murat Cirit8Alan J. Grodzinsky9Department of Biological Engineering, Massachusetts Institute of TechnologyDepartment of Biological Engineering, Massachusetts Institute of TechnologyDepartment of Biological Engineering, Massachusetts Institute of TechnologyDepartment of Clinical Sciences Lund, Orthopaedics, Faculty of Medicine, Lund UniversityDepartment of Biological Engineering, Massachusetts Institute of TechnologyDepartments of Pediatrics, Orthopedic Surgery and Medicine (Section of Rheumatology), Rush University Medical CenterDepartment of Orthopaedic Surgery, Indiana University School of MedicineDepartment of Developmental Biology, Harvard School of Dental MedicineJavelin BiotechDepartment of Biological Engineering, Massachusetts Institute of TechnologyAbstract Background Traumatic knee injuries in humans trigger an immediate increase in synovial fluid levels of inflammatory cytokines that accompany impact damage to joint tissues. We developed a human in vitro cartilage-bone-synovium (CBS) coculture model to study the role of mechanical injury and inflammation in the initiation of post-traumatic osteoarthritis (PTOA)-like disease. Methods Osteochondral plugs (cartilage-bone, CB) along with joint capsule synovium explants (S) were harvested from 25 cadaveric distal femurs from 16 human donors (Collin’s grade 0–2, 23–83years). Two-week monocultures (cartilage (C), bone (B), synovium (S)) and cocultures (CB, CBS) were established. A PTOA-like disease group was initiated via coculture of synovium explants with mechanically impacted osteochondral plugs (CBS+INJ, peak stress 5MPa) with non-impacted CB as controls. Disease-like progression was assessed through analyses of changes in cell viability, inflammatory cytokines released to media (10-plex ELISA), tissue matrix degradation, and metabolomics profile. Results Immediate increases in concentrations of a panel of inflammatory cytokines occurred in CBS+INJ and CBS cocultures and cultures with S alone (IL-1, IL-6, IL-8, and TNF-α among others). CBS+INJ and CBS also showed increased chondrocyte death compared to uninjured CB. The release of sulfated glycosaminoglycans (sGAG) and associated ARGS-aggrecan neoepitope fragments to the medium was significantly increased in CBS and CBS+INJ groups. Distinct metabolomics profiles were observed for C, B, and S monocultures, and metabolites related to inflammatory response in CBS versus CB (e.g., kynurenine, 1-methylnicotinamide, and hypoxanthine) were identified. Conclusion CBS and CBS+INJ models showed distinct cellular, inflammatory, and matrix-related alterations relevant to PTOA-like initiation/progression. The use of human knee tissues from donors that had no prior history of OA disease suggests the relevance of this model in highlighting the role of injury and inflammation in earliest stages of PTOA progression.https://doi.org/10.1186/s13075-022-02881-zPost-traumatic osteoarthritisInflammatory cytokinesOsteochondral-synovium cocultureCartilage mechanical injuryCartilage-bone-synovium metabolomicsGlycosaminoglycan |
| spellingShingle | Garima Dwivedi Lisa Flaman Begum Alaybeyoglu André Struglics Eliot H. Frank Susan Chubinskya Stephen B. Trippel Vicki Rosen Murat Cirit Alan J. Grodzinsky Inflammatory cytokines and mechanical injury induce post-traumatic osteoarthritis-like changes in a human cartilage-bone-synovium microphysiological system Arthritis Research & Therapy Post-traumatic osteoarthritis Inflammatory cytokines Osteochondral-synovium coculture Cartilage mechanical injury Cartilage-bone-synovium metabolomics Glycosaminoglycan |
| title | Inflammatory cytokines and mechanical injury induce post-traumatic osteoarthritis-like changes in a human cartilage-bone-synovium microphysiological system |
| title_full | Inflammatory cytokines and mechanical injury induce post-traumatic osteoarthritis-like changes in a human cartilage-bone-synovium microphysiological system |
| title_fullStr | Inflammatory cytokines and mechanical injury induce post-traumatic osteoarthritis-like changes in a human cartilage-bone-synovium microphysiological system |
| title_full_unstemmed | Inflammatory cytokines and mechanical injury induce post-traumatic osteoarthritis-like changes in a human cartilage-bone-synovium microphysiological system |
| title_short | Inflammatory cytokines and mechanical injury induce post-traumatic osteoarthritis-like changes in a human cartilage-bone-synovium microphysiological system |
| title_sort | inflammatory cytokines and mechanical injury induce post traumatic osteoarthritis like changes in a human cartilage bone synovium microphysiological system |
| topic | Post-traumatic osteoarthritis Inflammatory cytokines Osteochondral-synovium coculture Cartilage mechanical injury Cartilage-bone-synovium metabolomics Glycosaminoglycan |
| url | https://doi.org/10.1186/s13075-022-02881-z |
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