REVIEW

Cell Research (2008): 248-253
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Wnt signaling control of bone cell apoptosis

Peter V N Bodine

Correspondence: Peter V N Bodine Tel: +484-865-2717 Fax: +484-865-9368 Email: bodinep@wyeth.com

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Wnts are a large family of growth factors that mediate essential biological processes like embryogenesis, morphogenesis and organogenesis. These proteins also play a role in oncogenesis, and they regulate apoptosis in many tissues. Wnts bind to a membrane receptor complex comprised of a frizzled (FZD) G-protein-coupled receptor and a low-density lipoprotein (LDL) receptor-related protein (LRP). The formation of this ligand-receptor complex initiates a number of signaling cascades that include the canonical/beta-catenin pathway as well as several noncanonical pathways. In recent years, canonical Wnt signaling has been reported to play a significant role in the control of bone formation. Clinical studies have found that mutations in LRP-5 are associated with reduced bone mineral density (BMD) and fractures. Investigations of knockout and transgenic mouse models of Wnt pathway components have shown that canonical Wnt signaling modulates most aspects of osteoblast physiology including proliferation, differentiation, function and apoptosis. Transgenic mice expressing a gain of function mutant of LRP-5 in bone, or mice lacking the Wnt antagonist secreted frizzled-related protein-1, exhibit elevated BMD and suppressed osteoblast apoptosis. In addition, preclinical studies with pharmacologic compounds such as those that inhibit glycogen synthase kinase-3 support the importance of the canonical Wnt pathway in modulation of bone formation and osteoblast apoptosis.

Cell Research (2008) 18:248-253. doi: 10.1038/cr.2008.13; published online 22 January 2008

Keywords: LDL receptor-related protein, secreted frizzled-related protein, glycogen synthase kinase, osteoblast, bone formation, programmed cell death