FASEB journal : official publication of the Federation of American Societies for Experimental Biology
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We have evaluated the role of the ADP-ribosyl cyclase, CD38, in bone remodeling, a process by which the skeleton is being renewed constantly through the coordinated activity of osteoclasts and osteoblasts. CD38 catalyzes the cyclization of its substrate, NAD+, to the Ca2+-releasing second messenger, cyclic ADP-ribose (cADPr). We have shown previously that CD38 is expressed both in osteoblasts and osteoclasts. ⋯ Real-time RT-PCR on mRNA isolated from osteoclasts at day 6 showed a significant reduction in IL-6 and IL-6 receptor mRNA, together with significant decreases in the expression of all calcineurin A isoforms, alpha, beta, and gamma. These findings establish a critical role for CD38 in osteoclast formation and bone resorption. We speculate that CD38 functions as a cellular NAD+ "sensor," particularly during periods of active motility and secretion.
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The ex vivo effects of passive mechanical stretch on the activation of nuclear factor-kappaB (NF-kappaB) pathways in skeletal muscles from normal and mdx mouse, a model of Duchenne muscular dystrophy (DMD), were investigated. The NF-kappaB/DNA binding activity of the diaphragm muscle was increased by the application of axial mechanical stretch in a time-dependent manner. The increased activation of NF-kappaB was associated with a concomitant increase in I-kappaB (IkappaB) kinase activity and the degradation of IkappaBalpha protein. ⋯ Compared with normal diaphragm, the basal level of NF-kappaB activity was higher in muscles from mdx mice, and it was further enhanced in mechanically stretched muscles. Furthermore, activation of NF-kappaB and increased expression of inflammatory cytokines IL-1beta and tumor necrosis factor alpha in the mdx mouse precede the onset of muscular dystrophy. Our results show that mechanical stretch activates the classical NF-kappaB pathway and this pathway could be predominately active in DMD.