Transgenic disruption of glucocorticoid signaling in mature osteoblasts and osteocytes attenuates K/BxN mouse serum-induced arthritis in vivo

Autor: Colin R. Dunstan, Markus J. Seibel, Frank Buttgereit, Dörte Huscher, Ranier H. Straub, Cornelia M. Spies, Robert Kalak, Hong Zhou, James R.K. Modzelewski, Timo Gaber
Rok vydání: 2009
Předmět:
Zdroj: Arthritis & Rheumatism. 60:1998-2007
ISSN: 1529-0131
0004-3591
DOI: 10.1002/art.24619
Popis: Objective Endogenous glucocorticoids (GCs) modulate numerous biologic systems involved in the initiation and maintenance of arthritis. Bone cells play a critical role in the progression of arthritis, and some of the effects of GCs on inflammation may be mediated via these cells. The aim of this study was to investigate the impact of osteoblast-targeted disruption of GC signaling on joint inflammation, cartilage damage, and bone metabolism in the K/BxN mouse serum transfer model of autoimmune arthritis. Methods Intracellular GC signaling was disrupted in osteoblasts through transgenic overexpression of 11β-hydroxysteroid dehydrogenase type 2 under the control of a type I collagen promoter. Arthritis was induced in 5-week-old male transgenic mice and their wild-type (WT) littermates, and paw swelling was assessed daily until the mice were killed. The mice were examined by histology, histomorphometry, and microfocal computed tomography, and serum was analyzed for cytokines, adrenocorticotropic hormone, and corticosterone. Results Acute arthritis developed in both transgenic and WT mice treated with K/BxN mouse serum. However, the arthritis and local inflammatory activity were significantly attenuated in transgenic mice, as judged by clinical and histologic indices of inflammation and cartilage damage. Bone turnover and bone volume remained unchanged in arthritic transgenic mice, while WT mice exhibited stimulated bone resorption, suppressed osteoblast activity, and significantly reduced bone volume, compatible with the known effects of active inflammation on bone. Circulating levels of proinflammatory cytokines tended to be lower in arthritic transgenic mice than in control transgenic mice. Conclusion Disruption of GC signaling in osteoblasts significantly attenuates K/BxN mouse serum–induced autoimmune arthritis in mice. These data suggest that osteoblasts modulate the immune-mediated inflammatory response via a GC-dependent pathway.
Databáze: OpenAIRE
Externí odkaz: