WNT1 induced secreted protein-1 (WISP1) : A novel regulator of bone turnover and Wnt signaling [Molecular Bases of Disease]

April 11th, 2015 by Maeda, A., Ono, M., Holmbeck, K., Li, L., Kilts, T. M., Kram, V., Noonan, M. L., Yoshioka, Y., McNerny, E., Tantillo, M., Kohn, D., Lyons, K. M., Robey, P. G., Young, M. F.

WISP1/CCN4 (WISP1), a member of the CCN family is found in mineralized tissues and produced by osteoblasts and their precursors. In this study Wisp1 deficient (Wisp1-/-) mice were generated and using Dual Energy X-Ray Absorptiometry (DXA) showed that by three months the total bone mineral density (BMD) of Wisp1-/- mice was significantly lower than that of wild-type (WT) bones. Further investigation by micro computed tomography (μCT) showed that the bones from female Wisp1-/- mice had decreased trabecular bone volume/total volume (BV/TV) and that both male and female Wisp1-/- mice had decreased cortical bone thickness accompanied by diminished biomechanical strength. The molecular basis for decreased bone mass in Wisp1-/- mice arises from reduced bone formation likely caused by osteogenic progenitors that differentiate poorly compared to WT cells. Osteoclast precursors from Wisp1-/- mice developed more tartrate resistant acid phosphatase (TRAP) positive cells in vitro and in transplants suggesting Wisp1 is also negative regulator of osteoclast differentiation. When bone turnover (formation and resorption) was induced by ovariectomy Wisp1-/- mice had less BMD compared WT mice confirming the potential for multiple roles for WISP1 in controlling bone homeostasis. Wisp1-/- BMSCs had a reduced expression β-catenin and its target genes potentially caused by WISP1 inhibition of SOST binding to to LRP6. Taken together our data suggests that the decreased bone mass found in Wisp1-/- mice could, potentially, be caused by an insufficiency in the osteodifferentiation capacity of BMSCs arising from diminished Wnt signaling ultimately leading to altered bone turnover and weaker biomechanically compromised bones.