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

Abstract

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 11␤-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 seruminduced autoimmune arthritis in mice. These data suggest that osteoblasts modulate the immune-mediated inflammatory response via a GC-dependent pathway.Glucocorticoids (GCs) induce potent antiinflammatory and immunomodulatory effects when used therapeutically (1-4). Despite the clinical use of GCs for 60 years, new insights into their underlying mechanisms of action are still being gained, reflecting that the broad spectrum of GC effects is mediated by complex genomic and nongenomic actions (1-6). Much less is known about the role of endogenous GCs and their involvement in inflammatory conditions such as arthritis. Thus, Dr. Buttgereit

Glucocorticoid-Induced Osteoporosis in Growing Rats

“…It was also speculated that the increased bone fragility observed with GC treatment partially results from localized changes within the bone around the osteocyte [27]. In GC-treated mice, bone matrix mineralization and material properties are most profoundly affected in the perilacunar regions, suggesting an important role for osteocytes in bone metabolism [28]. In our future study, it is valuable to explore the relationship between osteocytes and GC and the underlying mechanism.…”

Contrast-enhanced nanofocus computed tomography images the cartilage subtissue architecture in three dimensions

“…Micro-CT has been reported frequently for imaging and assessing ex vivo the effect of different types of arthritis on the bone structure (Buttgereit et al, 2009;Herrak et al, 2004), surface roughness (Seeuws et al, 2010) and density (Healy et al, 2006). Although this technique allows investigation of the effect of arthritis on the underlying bone, nothing can be concluded concerning cartilage structure and functionality.…”

Neutrophils orchestrate their own recruitment in murine arthritis through C5aR and FcγR signaling

“…Osteoblasts are radiosensitive, express C5aR, and may modulate arthritis (29,30). To determine whether C5aR on osteoblasts contributes to arthritis, C5ar −/− recipients were reconstituted with BM from osteoblast-deficient (osteoprotegerin-deficient; Tnfrdf11b −/− ) mice.…”