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Stimulatory Effect of Tofacitinib on Bone Marrow Adipocytes Differentiation

BACKGROUND: Systemic inflammation is the main factor underlying secondary osteoporosis in patients with rheumatoid arthritis (RA). Janus kinase inhibitors (JAKi), such as tofacitinib (Tofa), can control systemic inflammation and may have beneficial effects on bone in various models. This might be du...

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Autores principales: Letarouilly, Jean-Guillaume, Paccou, Julien, Badr, Sammy, Chauveau, Christophe, Broux, Odile, Clabaut, Aline
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9299421/
https://www.ncbi.nlm.nih.gov/pubmed/35873000
http://dx.doi.org/10.3389/fendo.2022.881699
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author Letarouilly, Jean-Guillaume
Paccou, Julien
Badr, Sammy
Chauveau, Christophe
Broux, Odile
Clabaut, Aline
author_facet Letarouilly, Jean-Guillaume
Paccou, Julien
Badr, Sammy
Chauveau, Christophe
Broux, Odile
Clabaut, Aline
author_sort Letarouilly, Jean-Guillaume
collection PubMed
description BACKGROUND: Systemic inflammation is the main factor underlying secondary osteoporosis in patients with rheumatoid arthritis (RA). Janus kinase inhibitors (JAKi), such as tofacitinib (Tofa), can control systemic inflammation and may have beneficial effects on bone in various models. This might be due to direct effects on the bone microenvironment and not exclusively based on their anti-inflammatory function. Bone marrow adipocytes (BMAds) are abundant in the bone microenvironment. The effect of JAKi on BMAds is unknown, but evidence suggests that there is competition between human bone marrow-derived stromal cell (hBMSC) differentiation routes towards BMAds and osteoblasts (Ob) in osteoporosis. OBJECTIVES: The aims of the study are to determine whether Tofa influences BMAds and Ob derived from hBMSCs and to investigate the potential effects of Tofa on bone marrow adiposity in RA patients. METHODS: To determine the effect of Tofa on cellular commitment, hBMSCs were differentiated to BMAds or OBs for 3 days together with Tofa at 200, 400, or 800 nM and TNFα. This study was also conducted using differentiated BMAds. The impact of Tofa was determined by gene and protein expression analysis and cell density monitoring. In parallel, in a pilot study of 9 RA patients treated with Tofa 5 mg twice a day (NCT04175886), the proton density fat fraction (PDFF) was measured using MRI at the lumbar spine at baseline and at 6 months. RESULTS: In non-inflammatory conditions, the gene expression of Runx2 and Dlx5 decreased in Ob treated with Tofa (p <0.05). The gene expression of PPARγ2, C/EBPα, and Perilipin 1 were increased compared to controls (p <0.05) in BMAds treated with Tofa. Under inflammatory conditions, Tofa did not change the expression profiles of Ob compared to TNFα controls. In contrast, Tofa limited the negative effect of TNFα on BMAd differentiation (p <0.05). An increase in the density of differentiated BMAds treated with Tofa under TNFα was noted (p <0.001). These findings were consolidated by an increase in PDFF at 6 months of treatment with Tofa in RA patients (46.3 ± 7.0% versus 53.2 ± 9.2% p <0.01). CONCLUSION: Together, these results suggest a stimulatory effect of Tofa on BMAd commitment and differentiation, which does not support a positive effect of Tofa on bone.
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spelling pubmed-92994212022-07-21 Stimulatory Effect of Tofacitinib on Bone Marrow Adipocytes Differentiation Letarouilly, Jean-Guillaume Paccou, Julien Badr, Sammy Chauveau, Christophe Broux, Odile Clabaut, Aline Front Endocrinol (Lausanne) Endocrinology BACKGROUND: Systemic inflammation is the main factor underlying secondary osteoporosis in patients with rheumatoid arthritis (RA). Janus kinase inhibitors (JAKi), such as tofacitinib (Tofa), can control systemic inflammation and may have beneficial effects on bone in various models. This might be due to direct effects on the bone microenvironment and not exclusively based on their anti-inflammatory function. Bone marrow adipocytes (BMAds) are abundant in the bone microenvironment. The effect of JAKi on BMAds is unknown, but evidence suggests that there is competition between human bone marrow-derived stromal cell (hBMSC) differentiation routes towards BMAds and osteoblasts (Ob) in osteoporosis. OBJECTIVES: The aims of the study are to determine whether Tofa influences BMAds and Ob derived from hBMSCs and to investigate the potential effects of Tofa on bone marrow adiposity in RA patients. METHODS: To determine the effect of Tofa on cellular commitment, hBMSCs were differentiated to BMAds or OBs for 3 days together with Tofa at 200, 400, or 800 nM and TNFα. This study was also conducted using differentiated BMAds. The impact of Tofa was determined by gene and protein expression analysis and cell density monitoring. In parallel, in a pilot study of 9 RA patients treated with Tofa 5 mg twice a day (NCT04175886), the proton density fat fraction (PDFF) was measured using MRI at the lumbar spine at baseline and at 6 months. RESULTS: In non-inflammatory conditions, the gene expression of Runx2 and Dlx5 decreased in Ob treated with Tofa (p <0.05). The gene expression of PPARγ2, C/EBPα, and Perilipin 1 were increased compared to controls (p <0.05) in BMAds treated with Tofa. Under inflammatory conditions, Tofa did not change the expression profiles of Ob compared to TNFα controls. In contrast, Tofa limited the negative effect of TNFα on BMAd differentiation (p <0.05). An increase in the density of differentiated BMAds treated with Tofa under TNFα was noted (p <0.001). These findings were consolidated by an increase in PDFF at 6 months of treatment with Tofa in RA patients (46.3 ± 7.0% versus 53.2 ± 9.2% p <0.01). CONCLUSION: Together, these results suggest a stimulatory effect of Tofa on BMAd commitment and differentiation, which does not support a positive effect of Tofa on bone. Frontiers Media S.A. 2022-07-06 /pmc/articles/PMC9299421/ /pubmed/35873000 http://dx.doi.org/10.3389/fendo.2022.881699 Text en Copyright © 2022 Letarouilly, Paccou, Badr, Chauveau, Broux and Clabaut https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Endocrinology
Letarouilly, Jean-Guillaume
Paccou, Julien
Badr, Sammy
Chauveau, Christophe
Broux, Odile
Clabaut, Aline
Stimulatory Effect of Tofacitinib on Bone Marrow Adipocytes Differentiation
title Stimulatory Effect of Tofacitinib on Bone Marrow Adipocytes Differentiation
title_full Stimulatory Effect of Tofacitinib on Bone Marrow Adipocytes Differentiation
title_fullStr Stimulatory Effect of Tofacitinib on Bone Marrow Adipocytes Differentiation
title_full_unstemmed Stimulatory Effect of Tofacitinib on Bone Marrow Adipocytes Differentiation
title_short Stimulatory Effect of Tofacitinib on Bone Marrow Adipocytes Differentiation
title_sort stimulatory effect of tofacitinib on bone marrow adipocytes differentiation
topic Endocrinology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9299421/
https://www.ncbi.nlm.nih.gov/pubmed/35873000
http://dx.doi.org/10.3389/fendo.2022.881699
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