Administration of Cyclooxygenase-2 Inhibitor Reduces Joint Inflammation but Exacerbates Osteopenia in IL-1α Transgenic Mice Due to GM-CSF Overproduction

Abstract

IL-1α transgenic (Tg) mice exhibit chronic inflammatory arthritis and subsequent osteopenia, with IL-1-induced GM-CSF playing an important role in the pathogenesis. This study analyzed the mechanisms underlying osteopenia in Tg mice, and the therapeutic effects of the cyclooxygenase-2 inhibitor celecoxib on such osteopenia. Inhibited osteoclast formation was observed in RANKL-treated bone marrow cell (BMC) cultures from Tg mice and coculture of Tg-derived BMCs and wild-type-derived primary osteoblasts (POBs). FACS analysis indicated that this inhibition was attributable to a decreased number of osteoclast precursors within Tg-derived BMCs. Moreover, in coculture of Tg-derived POBs and either Tg- or wild-type-derived BMCs, osteoclast formation was markedly inhibited because Tg-derived POBs produced abundant GM-CSF, known as a potent inhibitor of osteoclast differentiation. Histomorphometric analysis of Tg mice revealed that both bone formation and resorption were decreased, with bone formation decreased more prominently. Interestingly, administration of celecoxib resulted in further deterioration of osteopenia where bone formation was markedly suppressed, whereas bone resorption remained unchanged. These results were explained by our in vitro observation that celecoxib dose-dependently and dramatically decreased osteogenesis by Tg mouse-derived POBs in culture, whereas mRNA expressions of GM-CSF and M-CSF remained unchanged. Consequently, blockade of PGE2 may exert positive effects on excessively enhanced bone resorption observed in inflammatory bone disease, whereas negative effects may occur mainly through reduced bone formation, when bone resorption is constitutively down-regulated as seen in Tg mice.

Optical tomographic imaging discriminates between disease-modifying anti-rheumatic drug (DMARD) and non-DMARD efficacy in collagen antibody-induced arthritis

“…Both p38 MAPK inhibitors and COX-2 inhibitors have previously been shown to effectively reduce clinical signs of disease and paw swelling measurements in rodent models of arthritis [6,7,51,52]. COX-2 inhibitors and other NSAIDs are better at providing symptom relief than at altering disease progression [10,11], however, whereas p38 MAPK inhibitors significantly decrease underlying inflammation and bone destruction [4-8].…”

Prostaglandins in bone: bad cop, good cop?

“…Cytokines can inhibit production of bone matrix proteins independently of cytokine-induced PG production, and it is possible that cytokine-induced PG production stimulates a compensatory anabolic effect. For example, in IL-1α transgenic mice, treatment in vivo with a COX-2 inhibitor reduced joint inflammation but increased osteopenia by suppressing bone formation [56]. …”

The granulocyte-macrophage colony-stimulating factor receptor: linking its structure to cell signaling and its role in disease

“…[107][108][109] The effects of blocking site 1 would be equivalent to blocking mAb directed against GM-CSF itself, many examples of which are currently in phase I and phase II clinical trials in autoimmune disease. Based largely on data from GM-CSF knockout animal models, site I antagonists would be expected to be of clinical value in certain inflammatory conditions and autoimmune diseases such as rheumatoid arthritis, [26][27][28]110 multiple sclerosis, [111][112][113] type I diabetes, and autoimmune glomerulonephritis. 114,115 Equivalent sites 1 in the IL-3R and IL-5R are also likely to be excellent targets.…”

“…In particular, murine models of rheumatoid arthritis and glomerulonephritis show a nonredundant role for GM-CSF in determining disease severity. [26][27][28] This dual role of the GM-CSF receptor in health and disease underscores the wide interest it has attracted in understanding its mechanism of action.…”