Hydroxytryptamine, 5- Receptors


Fig. arthritis; ETN, etanercept; RCI, repository corticotropin injection; SEM, standard error of the mean Table 1 Percent inhibition in disease parameters of individual and combination treatments in their joints, with Doxifluridine an increase in bone erosion and mature osteoclasts [38], which suggests that MCRs could modulate mediators that effect osteoclast number, differentiation, and function. Limitations of this study may include lack of an RCI dosing regimen that would provide maximum?clinical benefit, which has not been fully elucidated. RCI is usually a naturally sourced complex mixture of ACTH analogs and other pituitary peptides, so there could be multiple mechanisms of action that contribute to the response we see here. For example, the effects of RCI on reduced bone remodeling may be secondary as a result of anti-inflammatory properties. In addition, this study did not compare the effects of RCI with more conventional standard of care therapies, such as corticosteroids, which would be an important assessment for future research. Conclusions In summary, this is the first study to illustrate the benefits of RCI for inflammation and bone remodeling in established rat CIA, a preclinical model that exhibits joint inflammation and damage analogous to human RA [25]. When administered as adjunctive therapy with ETN, RCI additively reduced disease manifestations, including ankle edema and histopathologic measures of inflammation, pannus formation, cartilage damage, bone resorption, and periosteal bone formation. These preclinical data demonstrate a pivotal role for RCI in controlling inflammation and bone damage in immune-mediated arthritis and lend support to the efficacy of RCI in the treatment of patients with active RA. Supplementary information Additional file 1: Table S1. Experimental conditions. Fig. S1. Study design. Fig. S2. Analysis of body, spleen, and paw weight. Fig. S3. Histopathology images of the ankle. Fig. S4. Histologic analysis of joint damage in CIA. Fig. S5. IHC images displaying CD68-positive macrophages and cathepsin K-positive osteoclasts.(7.1M, docx) Acknowledgements We thank Bolder BioPath Inc. for conducting the rat CIA model. Editorial support and scientific consulting for this manuscript were provided by MedLogix Communications, LLC, Itasca, Illinois. Abbreviations RArheumatoid arthritisDMARDsdisease-modifying anti-rheumatic drugsTNFtumor necrosis factorETNetanerceptRCIrepository corticotropin injectionMCRmelanocortin receptorACTHadrenocorticotropic hormoneCIAcollagen-induced arthritismicro-CTmicrofocal computed tomographymgHAmagnesium hydroxyapatiteIHCimmunohistochemistryDAB3,3-diaminobenzidineCIIcollagen type IIIgGimmunoglobulin GELISAenzyme-linked immunosorbent assayANOVAanalysis of varianceNFBnuclear factor kappa-light-chain-enhancer of activated B cellsMSHalpha melanocyte-stimulating hormone Authors contributions DAD, PB, and PH conceived and designed the study. All authors interpreted the study results. CB and KH performed IHC and analyzed the data. DAD, PB, PH, and DW drafted the manuscript. All Doxifluridine authors read and approved the final manuscript. Funding These studies were funded by Mallinckrodt Pharmaceuticals. All authors are or were employees of Mallinckrodt Pharmaceuticals and were involved in the design of the study, the collection, analysis and interpretation of the data, and writing the manuscript. Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request Ethics approval and consent Doxifluridine to participate All Doxifluridine animal experiments were performed in accordance with the guidelines cited in the Guide for the Care and Use of Laboratory Animals [30]. The study protocol was reviewed and approved by the CD38 Institutional Animal Care and Use Committee of Mallinckrodt Pharmaceuticals. Consent for publication Not applicable. Competing interests These studies were funded by Mallinckrodt Pharmaceuticals, a registered business name of Mallinckrodt plc. At the time of the studies, all authors were employees of a Mallinckrodt company and stockholders of Mallinckrodt plc. Footnotes Publishers Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Supplementary information Supplementary information accompanies this paper at 10.1186/s12891-020-03609-3..