Abstract
BackgroundKMUP-1 is a xanthine derivative with inhibitory activities on the phosphodiesterase (PDE) 3,4 and 5 isoenzymes to suppress the degradation of cyclic AMP and cyclic GMP. However, the effects of KMUP-1 on osteoclast differentiation are still unclear. In this study, we investigated whether KMUP-1 inhibits osteoclastogenesis induced by RANKL in RAW 264.7 cells and bone loss induced by ovariectomy in mice, and the underlying mechanisms.Principal Findings In vitro, KMUP-1 inhibited RANKL-induced TRAP activity, the formation of multinucleated osteoclasts and resorption-pit formation. It also inhibited key mediators of osteoclastogenesis including IL-1β, IL-6, TNF-α and HMGB1. In addition, KMUP-1 inhibited RANKL-induced activation of signaling molecules (Akt, MAPKs, calcium and NF-κB), mRNA expression of osteoclastogensis-associated genes (TRAP, MMP-9, Fra-1, and cathepsin K) and transcription factors (c-Fos and NFATc1). Furthermore, most inhibitory effects of KMUP-1 on RANKL-mediated signal activations were reversed by a protein kinase A inhibitor (H89) and a protein kinase G inhibitor (KT5823). In vivo, KMUP-1 prevented loss of bone mineral content, preserved serum alkaline phosphate and reduced serum osteocalcin in ovariectomized mice.ConclusionsKMUP-1 inhibits RANKL-induced osteoclastogenesis in vitro and protects against ovariectomy-induced bone loss in vivo. These effects are mediated, at least in part, by cAMP and cGMP pathways. Therefore, KMUP-1 may have a role in pharmacologic therapy of osteoporosis.
Highlights
The metabolism of bone is dynamic status involving the resorption of bone by osteoclasts and the synthesis of bone matrix by osteoblasts [1]
KMUP-1 may have a role in pharmacologic therapy of osteoporosis
Receptor activator of NF-kB ligand (RANKL) (10 ng/ml) and KMUP-1 (0–10 mM). (A, C) Effects on activities of MMP-2 and matrix metalloproteinase-9 (MMP-9) were analyzed by gelatin zymography. (B, D) Effects on protein expressions of MMP-2 and MMP-9 were analyzed by Western blotting
Summary
The metabolism of bone is dynamic status involving the resorption of bone by osteoclasts and the synthesis of bone matrix by osteoblasts [1]. Factors that increase osteoclast formation or decrease osteoblast formation may enhance the process of osteoporosis. CAMP-specific PDE4 inhibitors pentoxifylline and rolipram can increase systemic bone-mass in mice [6,7]. Other PDE4 inhibitors XT-611 and XT-44 have been reported to increase osteoblast formation and decrease osteoclast formation in cultured mouse bone-marrow cells, and to prevent bone loss in the animal model of osteopenia [8,9]. The cGMP-specific PDE5 inhibitor zaprinast can inhibit osteoclast formation [10]. We investigated whether KMUP-1 inhibits osteoclastogenesis induced by RANKL in RAW 264.7 cells and bone loss induced by ovariectomy in mice, and the underlying mechanisms
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