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Noggin haploinsufficiency influences severity of arthritis in different mouse models
Arthritis Research & Therapyvolume 7, Article number: P118 (2005)
The severity and outcome of chronic arthritis is determined by the balance between destructive and homeostatic or anabolic molecular signaling pathways. Increasing evidence suggests a role for embryonic signaling pathways, essential for development and growth, in the maintenance of tissue homeostasis and in the induction of repair. Untimely or inappropriate activation of such pathways may also have a role in the progression of some diseases. Bone morphogenetic proteins (BMPs), originally identified as protein factors that induce a cascade of endochondral bone formation, have critical functions in cell proliferation, differentiation, adhesion and death. We have previously identified different BMPs in patients with chronic arthritis . In this study, we evaluate the effect of shifting the balance in BMP signaling by reducing endogenous levels of noggin, a BMP antagonist, in a mouse model of systemic auto-immune arthritis (collagen-induced arthritis [CIA]), a model of cartilage destruction (methylated BSA [mBSA]-induced monoarthritis) and a model of ankylosing enthesitis and spondyloarthritis (spontaneous arthritis in male DBA/1 mice).
Materials and methods
Heterozygous mice with a targeted inactivation of the noggin gene and insertion of a β-galactosidase reporter (noggin+/LacZ) (a gift from R Harland, Berkeley, USA), originally in the C57/Bl6 background, were back-crossed into the DBA/1 background for more than eight generations. mBSA-induced arthritis was induced by intra-articular mBSA injection on day 1, followed by injection of subcutaneous IL-1 on three consecutive days. Mice were sacrificed at day 7. Severity of disease was determined with a histological score based on exsudate, inflammatory cell infiltration in the synovium, pannus formation, cartilage and bone destruction. Cartilage destruction and proteoglycan loss was further quantified using safranin O staining and digital image analysis of the articular surfaces from tibia, patella and femur. CIA was induced by allo-immunisation with chicken type II collagen emulsified in complete Freund adjuvant on day 1, followed by intraperitoneal booster injection of type II collagen on day 21. Arthritis characterized by ankylosing enthesitis is spontaneously occurring in aging male DBA/1 mice after grouped caging (> 4 males per cage) from the age of 14 weeks onwards. Incidence and severity of arthritis was assessed clinically and by histology in the latter two models. Presence of noggin was determined by immunohistochemistry in wild-type mice and by LacZ staining in noggin+/LacZ mice.
Noggin haploinsufficiency did not affect the incidence or clinical severity of CIA in DBA/1 mice. No differences in histological severity were seen. The histological severity of mBSA-induced monoarthritis in noggin+/LacZ mice was similar to that of wild-type mice. However, cartilage destruction as determined by digital image analysis of proteoglycan content was significantly reduced in noggin+/LacZ mice suggesting a protective role for BMP signaling. Disease incidence and severity of spontaneous arthritis was similar in noggin+/LacZ and wild-type DBA/1 mice. However, histological analysis of this arthritis showed a slower disease progression in the haploinsufficient mice. Progression of ankylosing enthesitis, in particular chondrocyte hypertrophy and new bone formation, was delayed as compared with wild-type mice. The involvement of noggin in these processes was confirmed by immunohistochemistry for noggin in wild-type mice and LacZ staining in noggin+/LacZ mice.
Noggin haploinsufficiency has a protective effect on proteoglycan loss in a mouse model of cartilage destruction. Noggin haploinsufficiency also slows the progression of ankylosing enthesitis in a mouse model of spondyloarthritis. The role of noggin in ankylosing enthesitis is similar to what is seen during endochondral bone formation in development. These data provide further evidence that embryonic molecular signaling pathways, and BMP signaling in particular, are involved in the balance between tissue destruction, homeostasis and repair.
Lories RJ, et al: Bone morphogenetic proteins 2 and 6, expressed in arthritic synovium, are regulated by proinflammatory cytokines and differentially modulate fibroblast-like synoviocyte apoptosis. Arthritis Rheum. 2003, 48: 2807-2818. 10.1002/art.11389.
MD and RL contributed equally to this work. RJUL is the recipient of a post-doctoral fellowship from the Fund for Scientific Research Flanders. This work was supported by research grant 0.390.03 from the Fund for Scientific Research Flanders and a Bristol-Myers-Squibb EULAR Young Investigator Award to RJUL.