Matrix metalloproteinases and their tissue inhibitors as upcoming biomarker signatures of connective tissue diseases-related interstitial lung disease: towards an earlier and accurate diagnosis
Abstract Background Lack of understanding of interstitial lung disease (ILD) associated with systemic sclerosis (SSc) and rheumatoid arthritis (RA) hinders the early and accurate identification of these devastating diseases. Current clinical tools limitations highlight the need to complement them wi...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-02-01
|
| Series: | Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s10020-025-01128-2 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849723989970124800 |
|---|---|
| author | Verónica Pulito-Cueto Belén Atienza-Mateo Joao C. Batista-Liz María Sebastián Mora-Gil Víctor M. Mora-Cuesta David Iturbe-Fernández Sheila Izquierdo Cuervo Carolina Aguirre Portilla Ricardo Blanco Raquel López-Mejías |
| author_facet | Verónica Pulito-Cueto Belén Atienza-Mateo Joao C. Batista-Liz María Sebastián Mora-Gil Víctor M. Mora-Cuesta David Iturbe-Fernández Sheila Izquierdo Cuervo Carolina Aguirre Portilla Ricardo Blanco Raquel López-Mejías |
| author_sort | Verónica Pulito-Cueto |
| collection | DOAJ |
| description | Abstract Background Lack of understanding of interstitial lung disease (ILD) associated with systemic sclerosis (SSc) and rheumatoid arthritis (RA) hinders the early and accurate identification of these devastating diseases. Current clinical tools limitations highlight the need to complement them with accessible and non-invasive methods. Accordingly, we focused on identifying useful matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) as new biomarkers with clinical value in the diagnosis and prognosis of RA-ILD+ and SSc-ILD+. Methods Peripheral blood was collected from patients with RA-ILD+ (n = 49) and SSc-ILD+ (n = 38); as well as with RA-ILD- (n = 25), SSc-ILD- (n = 20) and idiopathic pulmonary fibrosis (IPF) (n = 39). MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-10, MMP-12, TIMP-1, and TIMP-2 serum levels were measured using xMAP Technology. Results Concerning early connective tissue disease (CTD)-ILD+ diagnosis, increased MMP-7, MMP-9, MMP-10, and MMP-12 levels were found in RA-ILD+ and SSc-ILD+ patients in relation to RA-ILD- and SSc-ILD- patients, respectively. RA-ILD+ patients showed higher MMP-2 levels and lower TIMP-1 levels than RA-ILD- patients. Interestingly, a reliable utility for identifying ILD in CTD was confirmed for the MMP-2, MMP-7, MMP-9, MMP-10, MMP-12, and TIMP-1 combination in RA and MMP-7, MMP-9, MMP-10, and MMP-12 combinatorial signature in SSc. Regarding accurate CTD-ILD+ diagnosis, RA-ILD+ and SSc-ILD+ patients showed lower MMP-7 and MMP-10 levels than IPF patients. Lower MMP-9 and TIMP-1 levels and higher MMP-3 levels were found in RA-ILD+ compared to IPF. Remarkably, effectively better differentiation between CTD-ILD+ and IPF was confirmed for a 5-biomarker signature consisting of MMP-3, MMP-7, MMP-9, MMP-10, and TIMP-1 in RA as well as for the MMP-7 and MMP-10 combination in SSc. Finally, in RA-ILD+ patients, higher MMP-10 levels were associated with worse pulmonary function, increased MMP-2 levels were related to the treatment with conventional synthetic disease-modifying anti-rheumatic drugs, and decreased TIMP-1 levels were linked with positivity rheumatoid factor status. Conclusions MMPs and TIMPs form combinatorial biomarker signatures with clinical value for non-invasive, early, and accurate diagnosis of RA-ILD+ and SSc-ILD+, constituting promising screening tools in clinical practice. |
| format | Article |
| id | doaj-art-0f70bda76ac644348db2626e5b51ae8f |
| institution | DOAJ |
| issn | 1528-3658 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Medicine |
| spelling | doaj-art-0f70bda76ac644348db2626e5b51ae8f2025-08-20T03:10:51ZengBMCMolecular Medicine1528-36582025-02-0131111410.1186/s10020-025-01128-2Matrix metalloproteinases and their tissue inhibitors as upcoming biomarker signatures of connective tissue diseases-related interstitial lung disease: towards an earlier and accurate diagnosisVerónica Pulito-Cueto0Belén Atienza-Mateo1Joao C. Batista-Liz2María Sebastián Mora-Gil3Víctor M. Mora-Cuesta4David Iturbe-Fernández5Sheila Izquierdo Cuervo6Carolina Aguirre Portilla7Ricardo Blanco8Raquel López-Mejías9Immunopathology Group, Marqués de Valdecilla University Hospital-IDIVALImmunopathology Group, Marqués de Valdecilla University Hospital-IDIVALImmunopathology Group, Marqués de Valdecilla University Hospital-IDIVALImmunopathology Group, Marqués de Valdecilla University Hospital-IDIVALImmunopathology Group, Marqués de Valdecilla University Hospital-IDIVALImmunopathology Group, Marqués de Valdecilla University Hospital-IDIVALImmunopathology Group, Marqués de Valdecilla University Hospital-IDIVALImmunopathology Group, Marqués de Valdecilla University Hospital-IDIVALImmunopathology Group, Marqués de Valdecilla University Hospital-IDIVALImmunopathology Group, Marqués de Valdecilla University Hospital-IDIVALAbstract Background Lack of understanding of interstitial lung disease (ILD) associated with systemic sclerosis (SSc) and rheumatoid arthritis (RA) hinders the early and accurate identification of these devastating diseases. Current clinical tools limitations highlight the need to complement them with accessible and non-invasive methods. Accordingly, we focused on identifying useful matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) as new biomarkers with clinical value in the diagnosis and prognosis of RA-ILD+ and SSc-ILD+. Methods Peripheral blood was collected from patients with RA-ILD+ (n = 49) and SSc-ILD+ (n = 38); as well as with RA-ILD- (n = 25), SSc-ILD- (n = 20) and idiopathic pulmonary fibrosis (IPF) (n = 39). MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-10, MMP-12, TIMP-1, and TIMP-2 serum levels were measured using xMAP Technology. Results Concerning early connective tissue disease (CTD)-ILD+ diagnosis, increased MMP-7, MMP-9, MMP-10, and MMP-12 levels were found in RA-ILD+ and SSc-ILD+ patients in relation to RA-ILD- and SSc-ILD- patients, respectively. RA-ILD+ patients showed higher MMP-2 levels and lower TIMP-1 levels than RA-ILD- patients. Interestingly, a reliable utility for identifying ILD in CTD was confirmed for the MMP-2, MMP-7, MMP-9, MMP-10, MMP-12, and TIMP-1 combination in RA and MMP-7, MMP-9, MMP-10, and MMP-12 combinatorial signature in SSc. Regarding accurate CTD-ILD+ diagnosis, RA-ILD+ and SSc-ILD+ patients showed lower MMP-7 and MMP-10 levels than IPF patients. Lower MMP-9 and TIMP-1 levels and higher MMP-3 levels were found in RA-ILD+ compared to IPF. Remarkably, effectively better differentiation between CTD-ILD+ and IPF was confirmed for a 5-biomarker signature consisting of MMP-3, MMP-7, MMP-9, MMP-10, and TIMP-1 in RA as well as for the MMP-7 and MMP-10 combination in SSc. Finally, in RA-ILD+ patients, higher MMP-10 levels were associated with worse pulmonary function, increased MMP-2 levels were related to the treatment with conventional synthetic disease-modifying anti-rheumatic drugs, and decreased TIMP-1 levels were linked with positivity rheumatoid factor status. Conclusions MMPs and TIMPs form combinatorial biomarker signatures with clinical value for non-invasive, early, and accurate diagnosis of RA-ILD+ and SSc-ILD+, constituting promising screening tools in clinical practice.https://doi.org/10.1186/s10020-025-01128-2Matrix metalloproteinasesMatrix metalloproteinases tissue inhibitorsInterstitial lung diseaseAutoimmune diseasesRheumatoid arthritisSystemic sclerosis |
| spellingShingle | Verónica Pulito-Cueto Belén Atienza-Mateo Joao C. Batista-Liz María Sebastián Mora-Gil Víctor M. Mora-Cuesta David Iturbe-Fernández Sheila Izquierdo Cuervo Carolina Aguirre Portilla Ricardo Blanco Raquel López-Mejías Matrix metalloproteinases and their tissue inhibitors as upcoming biomarker signatures of connective tissue diseases-related interstitial lung disease: towards an earlier and accurate diagnosis Molecular Medicine Matrix metalloproteinases Matrix metalloproteinases tissue inhibitors Interstitial lung disease Autoimmune diseases Rheumatoid arthritis Systemic sclerosis |
| title | Matrix metalloproteinases and their tissue inhibitors as upcoming biomarker signatures of connective tissue diseases-related interstitial lung disease: towards an earlier and accurate diagnosis |
| title_full | Matrix metalloproteinases and their tissue inhibitors as upcoming biomarker signatures of connective tissue diseases-related interstitial lung disease: towards an earlier and accurate diagnosis |
| title_fullStr | Matrix metalloproteinases and their tissue inhibitors as upcoming biomarker signatures of connective tissue diseases-related interstitial lung disease: towards an earlier and accurate diagnosis |
| title_full_unstemmed | Matrix metalloproteinases and their tissue inhibitors as upcoming biomarker signatures of connective tissue diseases-related interstitial lung disease: towards an earlier and accurate diagnosis |
| title_short | Matrix metalloproteinases and their tissue inhibitors as upcoming biomarker signatures of connective tissue diseases-related interstitial lung disease: towards an earlier and accurate diagnosis |
| title_sort | matrix metalloproteinases and their tissue inhibitors as upcoming biomarker signatures of connective tissue diseases related interstitial lung disease towards an earlier and accurate diagnosis |
| topic | Matrix metalloproteinases Matrix metalloproteinases tissue inhibitors Interstitial lung disease Autoimmune diseases Rheumatoid arthritis Systemic sclerosis |
| url | https://doi.org/10.1186/s10020-025-01128-2 |
| work_keys_str_mv | AT veronicapulitocueto matrixmetalloproteinasesandtheirtissueinhibitorsasupcomingbiomarkersignaturesofconnectivetissuediseasesrelatedinterstitiallungdiseasetowardsanearlierandaccuratediagnosis AT belenatienzamateo matrixmetalloproteinasesandtheirtissueinhibitorsasupcomingbiomarkersignaturesofconnectivetissuediseasesrelatedinterstitiallungdiseasetowardsanearlierandaccuratediagnosis AT joaocbatistaliz matrixmetalloproteinasesandtheirtissueinhibitorsasupcomingbiomarkersignaturesofconnectivetissuediseasesrelatedinterstitiallungdiseasetowardsanearlierandaccuratediagnosis AT mariasebastianmoragil matrixmetalloproteinasesandtheirtissueinhibitorsasupcomingbiomarkersignaturesofconnectivetissuediseasesrelatedinterstitiallungdiseasetowardsanearlierandaccuratediagnosis AT victormmoracuesta matrixmetalloproteinasesandtheirtissueinhibitorsasupcomingbiomarkersignaturesofconnectivetissuediseasesrelatedinterstitiallungdiseasetowardsanearlierandaccuratediagnosis AT daviditurbefernandez matrixmetalloproteinasesandtheirtissueinhibitorsasupcomingbiomarkersignaturesofconnectivetissuediseasesrelatedinterstitiallungdiseasetowardsanearlierandaccuratediagnosis AT sheilaizquierdocuervo matrixmetalloproteinasesandtheirtissueinhibitorsasupcomingbiomarkersignaturesofconnectivetissuediseasesrelatedinterstitiallungdiseasetowardsanearlierandaccuratediagnosis AT carolinaaguirreportilla matrixmetalloproteinasesandtheirtissueinhibitorsasupcomingbiomarkersignaturesofconnectivetissuediseasesrelatedinterstitiallungdiseasetowardsanearlierandaccuratediagnosis AT ricardoblanco matrixmetalloproteinasesandtheirtissueinhibitorsasupcomingbiomarkersignaturesofconnectivetissuediseasesrelatedinterstitiallungdiseasetowardsanearlierandaccuratediagnosis AT raquellopezmejias matrixmetalloproteinasesandtheirtissueinhibitorsasupcomingbiomarkersignaturesofconnectivetissuediseasesrelatedinterstitiallungdiseasetowardsanearlierandaccuratediagnosis |