Transgenic disruption of glucocorticoid signaling in mature osteoblasts and osteocytes attenuates K/BxN mouse serum-induced arthritis in vivo.
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 11beta-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.


CONCLUSIONS
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.
Buttgereit
Frank
F
ANZAC Research Institute, University of Sydney, Sydney, New South Wales, Australia.
Zhou
Hong
H
Kalak
Robert
R
Gaber
Timo
T
Spies
Cornelia M
CM
Huscher
Dörte
D
Straub
Ranier H
RH
Modzelewski
James
J
Dunstan
Colin R
CR
Seibel
Markus J
MJ
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000235:genetics / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D001168:Arthritis / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D001327:Autoimmune Diseases / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D001835:Body Weight / Q000502:physiology; D001842:Bone and Bones / Q000378:metabolism; D003345:Corticosterone / Q000097:blood; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D005938:Glucocorticoids / Q000378:metabolism*; D007596:Joints / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D010011:Osteocytes / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology*
D016207:Cytokines; D005938:Glucocorticoids; D000324:Adrenocorticotropic Hormone; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D003345:Corticosterone