The circadian regulator Bmal1 in joint mesenchymal cells regulates both joint development and inflammatory arthritis.
Arthritis
BMAL1
Chondrocyte
Circadian
Fibroblast-like synoviocytes
Macrophage
Synovium
Journal
Arthritis research & therapy
ISSN: 1478-6362
Titre abrégé: Arthritis Res Ther
Pays: England
ID NLM: 101154438
Informations de publication
Date de publication:
06 01 2019
06 01 2019
Historique:
received:
28
08
2018
accepted:
15
11
2018
entrez:
8
1
2019
pubmed:
8
1
2019
medline:
31
3
2020
Statut:
epublish
Résumé
The circadian clock plays a crucial role in regulating physiology and is important for maintaining immune homeostasis and responses to inflammatory stimuli. Inflammatory arthritis often shows diurnal variation in disease symptoms and disease markers, and it is now established that cellular clocks regulate joint inflammation. The clock gene Bmal1 is critical for maintenance of 24-h rhythms and plays a key role in regulating immune responses, as well as in aging-related processes. Fibroblast-like synoviocytes (FLS) are circadian rhythmic joint mesenchymal cells which are important for maintenance of joint health and play a crucial role in the development of inflammatory arthritis. The aim of this study was to investigate the importance of the joint mesenchymal cell circadian clock in health and disease. Mice were generated which lack Bmal1 in Col6a1-expressing cells, targeting mesenchymal cells in the ankle joints. Joints of these animals were assessed by X-ray imaging, whole-mount staining and histology, and the composition of the synovium was assessed by flow cytometry. Arthritis was induced using collagen antibodies. Bmal1 deletion in joint mesenchymal cells rendered the FLS and articular cartilage cells arrhythmic. Targeted mice exhibited significant changes in the architecture of the joints, including chondroid metaplasia (suggesting a switch of connective tissue stem cells towards a chondroid phenotype), reductions in resident synovial macrophages and changes in the basal pro-inflammatory activity of FLS. Loss of Bmal1 in FLS rendered these resident immune cells more pro-inflammatory in response to challenge, leading to increased paw swelling, localised infiltration of mononuclear cells and enhanced cytokine production in a model of arthritis. This study demonstrates the importance of Bmal1 in joint mesenchymal cells in regulating FLS and chondrocyte development. Additionally, we have identified a role for this core clock component for restraining local responses to inflammation and highlight a role for the circadian clock in regulating inflammatory arthritis.
Sections du résumé
BACKGROUND
The circadian clock plays a crucial role in regulating physiology and is important for maintaining immune homeostasis and responses to inflammatory stimuli. Inflammatory arthritis often shows diurnal variation in disease symptoms and disease markers, and it is now established that cellular clocks regulate joint inflammation. The clock gene Bmal1 is critical for maintenance of 24-h rhythms and plays a key role in regulating immune responses, as well as in aging-related processes. Fibroblast-like synoviocytes (FLS) are circadian rhythmic joint mesenchymal cells which are important for maintenance of joint health and play a crucial role in the development of inflammatory arthritis. The aim of this study was to investigate the importance of the joint mesenchymal cell circadian clock in health and disease.
METHODS
Mice were generated which lack Bmal1 in Col6a1-expressing cells, targeting mesenchymal cells in the ankle joints. Joints of these animals were assessed by X-ray imaging, whole-mount staining and histology, and the composition of the synovium was assessed by flow cytometry. Arthritis was induced using collagen antibodies.
RESULTS
Bmal1 deletion in joint mesenchymal cells rendered the FLS and articular cartilage cells arrhythmic. Targeted mice exhibited significant changes in the architecture of the joints, including chondroid metaplasia (suggesting a switch of connective tissue stem cells towards a chondroid phenotype), reductions in resident synovial macrophages and changes in the basal pro-inflammatory activity of FLS. Loss of Bmal1 in FLS rendered these resident immune cells more pro-inflammatory in response to challenge, leading to increased paw swelling, localised infiltration of mononuclear cells and enhanced cytokine production in a model of arthritis.
CONCLUSIONS
This study demonstrates the importance of Bmal1 in joint mesenchymal cells in regulating FLS and chondrocyte development. Additionally, we have identified a role for this core clock component for restraining local responses to inflammation and highlight a role for the circadian clock in regulating inflammatory arthritis.
Identifiants
pubmed: 30612576
doi: 10.1186/s13075-018-1770-1
pii: 10.1186/s13075-018-1770-1
pmc: PMC6322248
doi:
Substances chimiques
ARNTL Transcription Factors
0
Bmal1 protein, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5Subventions
Organisme : Medical Research Council
ID : MR/L018640/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/P023576/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N00583X/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/M008908/1
Pays : United Kingdom
Organisme : Versus Arthritis
ID : 20629
Pays : United Kingdom
Organisme : Arthritis Research UK
ID : 20619
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 107851/Z/15/Z
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Références
Dev Biol. 2008 Apr 1;316(1):62-73
pubmed: 18295755
J Anat. 2012 Dec;221(6):480-96
pubmed: 22686699
Biochem Biophys Res Commun. 2018 Jan 8;495(2):1675-1680
pubmed: 29217191
Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5339-46
pubmed: 14963227
J Immunol. 2008 Apr 15;180(8):5707-19
pubmed: 18390756
J Exp Med. 2008 Feb 18;205(2):331-7
pubmed: 18250193
JCI Insight. 2018 Apr 5;3(7):
pubmed: 29618659
Immunol Rev. 2010 Jan;233(1):233-55
pubmed: 20193003
J Immunol. 1997 Jun 1;158(11):5507-13
pubmed: 9164974
Endocrinology. 2009 Jan;150(1):268-76
pubmed: 18787022
Acta Neuropathol. 2015 Jan;129(1):97-113
pubmed: 25421425
Ann Rheum Dis. 2018 Oct;77(10):1490-1497
pubmed: 29959183
Genesis. 2005 Mar;41(3):122-32
pubmed: 15739187
Genes Dev. 2006 Jul 15;20(14):1868-73
pubmed: 16847346
J Clin Invest. 2016 Jan;126(1):365-76
pubmed: 26657859
Proc Natl Acad Sci U S A. 2016 Sep 6;113(36):10085-90
pubmed: 27528682
Cell Rep. 2014 Oct 23;9(2):591-604
pubmed: 25373902
Cell. 2000 Dec 22;103(7):1009-17
pubmed: 11163178
Arthritis Rheum. 2007 Jul;56(7):2244-54
pubmed: 17599735
J Cell Sci. 2008 Nov 1;121(Pt 21):3629-35
pubmed: 18946026
Mol Med Rep. 2017 Jul;16(1):422-428
pubmed: 28498398
J Intern Med. 2015 May;277(5):513-27
pubmed: 25599827
FASEB J. 2016 Nov;30(11):3759-3770
pubmed: 27488122
Science. 2013 Sep 27;341(6153):1483-8
pubmed: 23970558
Sci Rep. 2017 Aug 31;7(1):10133
pubmed: 28860618
Arch Histol Cytol. 2000 Mar;63(1):17-31
pubmed: 10770586
Life Sci. 2006 Jul 17;79(8):764-71
pubmed: 16616208
Sci Transl Med. 2016 Feb 3;8(324):324ra16
pubmed: 26843191
Proc Natl Acad Sci U S A. 2012 Jan 10;109(2):582-7
pubmed: 22184247
PLoS One. 2013;8(1):e54049
pubmed: 23335987
Science. 2006 Nov 24;314(5803):1304-8
pubmed: 17124323
Methods Mol Biol. 2014;1130:113-121
pubmed: 24482169
Nat Rev Immunol. 2018 Jul;18(7):423-437
pubmed: 29662121
Arthritis Res Ther. 2007;9(5):220
pubmed: 18001488
Sci Rep. 2016 Sep 08;6:33027
pubmed: 27604178
RMD Open. 2017 Dec 6;3(2):e000527
pubmed: 29299338
Nat Med. 2014 Aug;20(8):919-26
pubmed: 25064128
Acta Histochem. 2014 Sep;116(7):1199-207
pubmed: 25109449
J Cell Biol. 1996 Nov;135(4):1163-77
pubmed: 8922394
Arthritis Res Ther. 2012 May 23;14(3):R122
pubmed: 22621205
Ann Rheum Dis. 2017 Mar;76(3):576-584
pubmed: 27489225