Alterations in the self-renewal and differentiation ability of bone marrow mesenchymal stem cells in a mouse model of rheumatoid arthritis.
BACKGROUND
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease primarily involving the synovium. Evidence in recent years has suggested that the bone marrow (BM) may be involved, and may even be the initiating site of the disease. Abnormalities in haemopoietic stem cells' (HSC) survival, proliferation and aging have been described in patients affected by RA and ascribed to abnormal support by the BM microenvironment. Mesenchymal stem cells (MSC) and their progeny constitute important components of the BM niche. In this study we test the hypothesis that the onset of inflammatory arthritis is associated with altered self-renewal and differentiation of bone marrow MSC, which alters the composition of the BM microenvironment.


METHODS
We have used Balb/C Interleukin-1 receptor antagonist knock-out mice, which spontaneously develop RA-like disease in 100% of mice by 20 weeks of age to determine the number of mesenchymal progenitors and their differentiated progeny before, at the start and with progression of the disease.


RESULTS
We showed a decrease in the number of mesenchymal progenitors with adipogenic potential and decreased bone marrow adipogenesis before disease onset. This is associated with a decrease in osteoclastogenesis. Moreover, at the onset of disease a significant increase in all mesenchymal progenitors is observed together with a block in their differentiation to osteoblasts. This is associated with accelerated bone loss.


CONCLUSIONS
Significant changes occur in the BM niche with the establishment and progression of RA-like disease. Those changes may be responsible for aspects of the disease, including the advance of osteoporosis. An understanding of the molecular mechanisms leading to those changes may lead to new strategies for therapeutic intervention.
Mohanty
Sindhu T
ST
Department of Human Metabolism, University of Sheffield, Sheffield S10 2RX, UK. s.t.Mohanty@shef.ac.uk
Kottam
Lucksy
L
Gambardella
Alessandra
A
Nicklin
Martin J
MJ
Coulton
Les
L
Hughes
David
D
Wilson
Anthony G
AG
Croucher
Peter I
PI
Bellantuono
Ilaria
I
D050156:Adipogenesis / Q000276:immunology; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000473:pathology*; D001854:Bone Marrow Cells / Q000276:immunology / Q000473:pathology*; D002454:Cell Differentiation / Q000276:immunology; D019070:Cell Lineage / Q000276:immunology; D004195:Disease Models, Animal; D018450:Disease Progression; D059630:Mesenchymal Stem Cells / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010010:Osteoclasts / Q000276:immunology / Q000473:pathology; D017472:Receptors, Interleukin-1 / Q000235:genetics; D013583:Synovial Membrane / Q000276:immunology / Q000473:pathology
D017472:Receptors, Interleukin-1