Abstract
Background The vasoactive neuropeptide calcitonin gene-related peptide alpha (αCGRP) enhances nociceptionin primary knee osteoarthritis (OA) and has been shown to disrupt cartilage and joint integrity in experimental rheu-matoid arthritis (RA). Little is known about how αCGRP may alter articular structures in primary OA. We investigatedwhether αCGRP modulates local inflammation and concomitant cartilage and bone changes in a murine modelof age-dependent OA.Methods Sixteen- to 18-month-old αCGRP-deficient mice (αCGRP−/−aged) were compared to, first, age-matchedwild type (WT aged) and, second, young 4- to 5-month-old non-OA αCGRP-deficient (αCGRP−/−CTRL) and non-OA WTanimals (WT CTRL). αCGRP levels were measured in serum. Knee and hip joint inflammation, cartilage degradation,and bone alterations were assessed by histology (OARSI histopathological grading score), gene expression analysis,and μ-computed tomography.Results WTaged mice exhibited elevated αCGRP serum levels compared to young WTCTRL animals. Marked signsof OA-induced cartilage destruction were seen in WT aged animals, while αCGRP−/−aged mice were mostly protectedfrom this effect. Age-dependent OA was accompanied by an increased gene expression of pro-inflammatory Tnfa,Il1b, and Il6 and catabolic Mmp13, Adamts5, Ctsk, Tnfs11 (Rankl), and Cxcl12/Cxcr4 in WTaged but not in αCGRP−/−agedmice. αCGRP-deficiency however further aggravated subchondral bone sclerosis of the medial tibial plateauand accelerated bone loss in the epi- and metaphyseal trabecular tibial bone in age-dependent OA.Conclusions Similar to its function in experimental RA, αCGRP exerts a dual pro-inflammatory and bone-protectivefunction in murine primary OA. Although anti-CGRP treatment was previously not successful in reducing pain in OAclinically, these data underline a crucial pathophysiological role of αCGRP in age-related OA.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 244 |
| Tidsskrift | Arthritis Research and Therapy |
| Vol/bind | 25 |
| Antal sider | 11 |
| ISSN | 1478-6354 |
| DOI | |
| Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:Open Access funding enabled and organized by Projekt DEAL. This work was supported by the Stiftung Oskar-Helene-Heim (OHH) to TM; the Else Kröner-Fresenius-Stiftung (EKFS 2017_A22) to JK; the Deutsche Forschungsgemeinschaft (DFG KE 2179/2–1, TS 303/2–1) to JK and ST. This study was partly funded by the DFG Collaborative Research Center 1444 and the European Union under Grant Agreement Nr. 101095635 (PROTO). Views and opinions expressed are however those of the authors only and do not necessarily reflect those of the European Union or the European Health and Digital Executive Agency (HADEA). Neither the European Union nor the granting authority can be held responsible for them.
Funding Information:
TM is a participant in the BIH Charité Clinician Scientist Program funded by the Charité – Universitätsmedizin Berlin, and the Berlin Institute of Health at Charité (BIH). The authors want to thank Juliane Unger and her team of animal caretakers at the Forschungseinrichtung für Experimentelle Medizin (FEM, Charité – Universitätsmedizin Berlin, Germany) for their assistance in the project. We further want to thank Ulrike Weichelt for her assistance in performing the serum analysis.
Funding Information:
TM is a participant in the BIH Charité Clinician Scientist Program funded by the Charité – Universitätsmedizin Berlin, and the Berlin Institute of Health at Charité (BIH). The authors want to thank Juliane Unger and her team of animal caretakers at the Forschungseinrichtung für Experimentelle Medizin (FEM, Charité – Universitätsmedizin Berlin, Germany) for their assistance in the project. We further want to thank Ulrike Weichelt for her assistance in performing the serum analysis.
Publisher Copyright:
© 2023, The Author(s).