Micro-CT imaging analysis for the effect of celecoxib, a cyclooxygenase-2 inhibitor, on inflammatory bone destruction in adjuvant arthritis rats

Abstract

Cyclooxygenase (COX)-2 is known to play an important role in the differentiation and maturation of osteoclasts. However, the role of COX-1 in bone metabolism has not been well explored. In this study, the bone-conserving effects of COX-2-specific (celecoxib), COX-nonselective (loxoprofen), and COX-1-specific agents (SC-58560) were compared using an adjuvant-induced arthritis (AIA) rat model. Arthritis was induced by injecting 50 microl liquid paraffin containing 1 mg Mycobacterium butyricum into the left footpad of Lewis rats. Drugs were given orally twice daily for 10 days beginning 15 days after adjuvant injection. Celecoxib was administered at the rate of 3 mg/kg per day, loxoprofen at 3 mg/kg per day, and SC-58560 at 10 mg/kg per day. The therapeutic effects on 3-D architectural bone changes in the arthritic condition, e.g., the bone volume/total tissue volume ratio and the amount of trabecular bone pattern factor, were determined by analyzing the hindpaw calcaneus of AIA rats using microcomputed tomography (micro-CT). In addition, dual-energy X-ray absorptiometry 2-D bone analysis was performed to compare with micro-CT analysis. AIA rats are prone to substantial bone erosion, which allows for significant changes in the 3-D architectural index. This inflammatory bone destruction was suppressed potently by celecoxib, only moderately by loxoprofen, and not at all by SC-58560. These data suggest that COX-2 plays an important role in the inflammatory bone destruction that occurs with rheumatoid arthritis. The results also suggest that COX-2 is more effective than COX-1 at suppressing the destruction of bone associated with arthritis.

A multiparameter approach to monitor disease activity in collagen-induced arthritis

“…Second, for the assessment of bone erosions, we introduced a rather new method that is based on micro-CT imaging and allows objective and high throughput analyses. So far, bone loss on micro-CT was mainly studied using parameters describing bone volume and composition [22,23]. A major hallmark of RA and CIA, however, is the appearance of focal bone erosions [24] and to quantify these erosions we calculated the number of objects on slices through the calcaneus as a measure for bone fragmentation.…”

Rodent Preclinical Models for Developing Novel Antiarthritic Molecules: Comparative Biology and Preferred Methods for Evaluating Efficacy

“…Extra-articular tissues (especially hematopoietic organs like bone marrow, lymph nodes, or spleen) may be isolated to correlate tissue leukocyte numbers to circulating cell counts by flow cytometry or histopathology [93, 94] or to permit evaluation of systemic bone loss at sites distant from affected joints (e.g., lumbar vertebrae [10]). Diseased joints may be imaged using conventional radiography [105], computed tomography [26, 157, 158], or magnetic resonance imaging [157]. Paws may be harvested and split longitudinally while fresh using a circular, water-cooled diamond saw (e.g., Isomet Low Speed model; Buehler, Lake Bluff, IL) to provide for more rapid penetration of fixative; subsequent fixation time can be reduced substantially, thereby reducing the degradation of delicate antigens and nucleic acids while retaining good tissue morphology.…”

Celecoxib: considerations regarding its potential disease-modifying properties in osteoarthritis

“…Various studies have shown a beneficial effect of celecoxib on bone in vivo [12,88-90]. Celecoxib, but not other NSAIDs, reduced bone mineral density loss [12,88,90] and enhanced trabecular bone volume in adjuvant- and collagen-induced arthritis in rats [88-90].…”

“…Celecoxib, but not other NSAIDs, reduced bone mineral density loss [12,88,90] and enhanced trabecular bone volume in adjuvant- and collagen-induced arthritis in rats [88-90]. The increased trabecular bone volume correlated with reduced serum type I collagen C-telopeptide, a bone resorption marker representing osteoclast activity [12,88], and other bone resorption parameters [89]. Whereas celecoxib did not affect bone formation, it suppressed osteoclast numbers in tibia of arthritic animals [89,90].…”