Anti-WISP2 monoclonal antibody, clone 2F22

Although the intermittent administration of PTH is known to stimulate the bone formation, the underlying mechanisms are not fully understood. Here we investigated the crosstalk between PTH/cAMP signaling and canonical Wnt signaling using the human osteoblastic cell line Saos-2. Treatment with PTH or forskolin, an activator of adenylate cyclase, facilitated T-cell factor (TCF)-dependent transactivation in a dose-dependent manner, which was abolished by pre-treatment with a PKA inhibitor, H89. Wnt3a and forskolin synergistically increased the TCF-dependent transactivation. Interestingly intermittent treatment with PTH enhanced the TCF-dependent transactivation more profoundly than continuous treatment. In addition to the effects on TCF-dependent reporter activity, treatment with PTH or forskolin resulted in the increased expression ofendogenous targets of Wnts, Wnt-induced secreted protein 2 (WISP2) and naked cuticle 2 (NKD2). We then investigated the convergence point of PTH/cAMP signaling and the canonical Wnt pathway. Western blotting demonstrated that GSK-3 beta was rapidly phosphorylated at Ser(9) on treatment with PTH or forskolin, leading to its inactivation. Moreover, overexpression of a constitutively active mutant of GSK-3 beta abolished the TCF-dependent transactivation induced by forskolin. On the other hand, overexpression of the Wnt antagonist Dickkopf-1 (DKK1) failed to cancel the effects of forskolin on the canocical Wnt pathway. Interestingly, treatment with Wnt3a markedly reduced the forskolin-induced expression of receptor activaror of NF-kappa B ligand (RANKL), a target gene of PTH/cAMP/PKA. these results suggest that cAMP/PKA signaling activates the canonical Wnt pathway through the inactivation of GSK-3 beta, whereas Wnt signaling might inhibit bone resorption through a negative impact on RANKL expression in osteoblasts. J. Cell. biochem. 104: 304-317, 2008. (C) 2007 Wiley-Liss. Inc.

There is no treatment for fibrotic disease is a significant cause of mortality. CCN2 Members of the CCN family of matricellular proteins have a characteristic four domain structure. CCN2 (connective tissue growth factor) is believed to play an essential role in fibrogenesis. In a recent paper, data are provided that CCN5 (wisp2), which lacks the carboxy-terminal heparin-binding domain shared by the other CCN proteins, may act as a dominant-negative protein to suppress CCN2-mediated fibrogenesis. These data are consistent with the notion that different CCN proteins may enhance or suppress each other's action and also suggest that CCN5, may be used as a novel anti-fibrotic therapy.