Methotrexate inhibits BMP4 and abrogates the hypertrophic chondrocyte phenotype of synovial fibroblasts in juvenile idiopathic arthritis
Abstract Background Juvenile Idiopathic Arthritis (JIA) induces growth disturbances in affected joints. Fibroblast-like synoviocytes (FLS) play a crucial role in JIA pathogenesis. FLS overexpress bone morphogenetic protein 4 (BMP4) and have a chondrocyte-like phenotype. FLS contribute directly to jo...
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| Format: | Article |
| Language: | English |
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BMC
2024-01-01
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| Series: | Pediatric Rheumatology Online Journal |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12969-023-00940-6 |
| _version_ | 1827388653794492416 |
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| author | Megan M. Simonds Samuel T. Freer Anne Marie C. Brescia |
| author_facet | Megan M. Simonds Samuel T. Freer Anne Marie C. Brescia |
| author_sort | Megan M. Simonds |
| collection | DOAJ |
| description | Abstract Background Juvenile Idiopathic Arthritis (JIA) induces growth disturbances in affected joints. Fibroblast-like synoviocytes (FLS) play a crucial role in JIA pathogenesis. FLS overexpress bone morphogenetic protein 4 (BMP4) and have a chondrocyte-like phenotype. FLS contribute directly to joint growth disturbances through endochondral bone formation. We investigated the ability of methotrexate to inhibit BMP4 expression and alter the hypertrophic chondrocyte-like phenotype of JIA FLS. Methods We selected primary cells from three subjects with persistent oligoarticular JIA, three subjects who eventually extended to a polyarticular disease course, which we termed extended-to-be (ETB), and three subjects who had polyarticular arthritis at time of diagnosis. We treated cells with methotrexate and two BMP4 inhibitors: noggin and chordin. We measured protein concentration from three chondrocyte cell markers: collagen II, aggrecan, and collagen X as well as BMP4. Results ColX, marker of chondrocyte hypertrophy, was significantly increased in polyarticular FLS when compared to both persistent FLS and ETB FLS, making polyarticular FLS the most like hypertrophic chondrocytes. Methotrexate caused significant decreases in BMP4 and ColX expression in persistent, ETB, and polyarticular FLS when compared to respective untreated cells. Ligand-binding BMP4 antagonists, noggin and chordin, caused significant decreases in ColX expression in FLS from all three disease courses and significant increases in collagen II protein, an early chondrocyte marker, when compared to respective untreated cells. Conclusions Methotrexate, the first-line therapy in the treatment of JIA, mimics BMP4 antagonists by effectively lowering BMP4 and ColX expression in FLS. Inhibiting FLS from undergoing hypertrophy could prevent these cells from contributing to joint growth disturbances via endochondral bone formation. |
| first_indexed | 2024-03-08T16:22:00Z |
| format | Article |
| id | doaj.art-0c970fe87ca345f09b4b6dd2441dfedf |
| institution | Directory Open Access Journal |
| issn | 1546-0096 |
| language | English |
| last_indexed | 2024-03-08T16:22:00Z |
| publishDate | 2024-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Pediatric Rheumatology Online Journal |
| spelling | doaj.art-0c970fe87ca345f09b4b6dd2441dfedf2024-01-07T12:15:37ZengBMCPediatric Rheumatology Online Journal1546-00962024-01-012211810.1186/s12969-023-00940-6Methotrexate inhibits BMP4 and abrogates the hypertrophic chondrocyte phenotype of synovial fibroblasts in juvenile idiopathic arthritisMegan M. Simonds0Samuel T. Freer1Anne Marie C. Brescia2Nemours Biomedical ResearchNemours Biomedical ResearchNemours Children’s Health, DelawareAbstract Background Juvenile Idiopathic Arthritis (JIA) induces growth disturbances in affected joints. Fibroblast-like synoviocytes (FLS) play a crucial role in JIA pathogenesis. FLS overexpress bone morphogenetic protein 4 (BMP4) and have a chondrocyte-like phenotype. FLS contribute directly to joint growth disturbances through endochondral bone formation. We investigated the ability of methotrexate to inhibit BMP4 expression and alter the hypertrophic chondrocyte-like phenotype of JIA FLS. Methods We selected primary cells from three subjects with persistent oligoarticular JIA, three subjects who eventually extended to a polyarticular disease course, which we termed extended-to-be (ETB), and three subjects who had polyarticular arthritis at time of diagnosis. We treated cells with methotrexate and two BMP4 inhibitors: noggin and chordin. We measured protein concentration from three chondrocyte cell markers: collagen II, aggrecan, and collagen X as well as BMP4. Results ColX, marker of chondrocyte hypertrophy, was significantly increased in polyarticular FLS when compared to both persistent FLS and ETB FLS, making polyarticular FLS the most like hypertrophic chondrocytes. Methotrexate caused significant decreases in BMP4 and ColX expression in persistent, ETB, and polyarticular FLS when compared to respective untreated cells. Ligand-binding BMP4 antagonists, noggin and chordin, caused significant decreases in ColX expression in FLS from all three disease courses and significant increases in collagen II protein, an early chondrocyte marker, when compared to respective untreated cells. Conclusions Methotrexate, the first-line therapy in the treatment of JIA, mimics BMP4 antagonists by effectively lowering BMP4 and ColX expression in FLS. Inhibiting FLS from undergoing hypertrophy could prevent these cells from contributing to joint growth disturbances via endochondral bone formation.https://doi.org/10.1186/s12969-023-00940-6Juvenile idiopathic arthritisMethotrexateBone morphogenetic protein 4SynoviocytesChondrocytes |
| spellingShingle | Megan M. Simonds Samuel T. Freer Anne Marie C. Brescia Methotrexate inhibits BMP4 and abrogates the hypertrophic chondrocyte phenotype of synovial fibroblasts in juvenile idiopathic arthritis Pediatric Rheumatology Online Journal Juvenile idiopathic arthritis Methotrexate Bone morphogenetic protein 4 Synoviocytes Chondrocytes |
| title | Methotrexate inhibits BMP4 and abrogates the hypertrophic chondrocyte phenotype of synovial fibroblasts in juvenile idiopathic arthritis |
| title_full | Methotrexate inhibits BMP4 and abrogates the hypertrophic chondrocyte phenotype of synovial fibroblasts in juvenile idiopathic arthritis |
| title_fullStr | Methotrexate inhibits BMP4 and abrogates the hypertrophic chondrocyte phenotype of synovial fibroblasts in juvenile idiopathic arthritis |
| title_full_unstemmed | Methotrexate inhibits BMP4 and abrogates the hypertrophic chondrocyte phenotype of synovial fibroblasts in juvenile idiopathic arthritis |
| title_short | Methotrexate inhibits BMP4 and abrogates the hypertrophic chondrocyte phenotype of synovial fibroblasts in juvenile idiopathic arthritis |
| title_sort | methotrexate inhibits bmp4 and abrogates the hypertrophic chondrocyte phenotype of synovial fibroblasts in juvenile idiopathic arthritis |
| topic | Juvenile idiopathic arthritis Methotrexate Bone morphogenetic protein 4 Synoviocytes Chondrocytes |
| url | https://doi.org/10.1186/s12969-023-00940-6 |
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