WNT1-induced Secreted Protein-1 (WISP1), a Novel Regulator of Bone Turnover and Wnt Signaling

WISP1/CCN4 (hereafter referred to as WISP1), a member of the CCN family, is found in mineralized tissues and is produced by osteoblasts and their precursors. In this study, Wisp1-deficient (Wisp1−/−) mice were generated. Using dual-energy x-ray absorptiometry, we showed that by 3 months, the total b...

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Published in:	The Journal of biological chemistry Vol. 290; no. 22; pp. 14004 - 14018
Main Authors:	Maeda, Azusa, Ono, Mitsuaki, Holmbeck, Kenn, Li, Li, Kilts, Tina M., Kram, Vardit, Noonan, Megan L., Yoshioka, Yuya, McNerny, Erin M.B., Tantillo, Margaret A., Kohn, David H., Lyons, Karen M., Robey, Pamela G., Young, Marian F.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 29-05-2015 American Society for Biochemistry and Molecular Biology
Subjects:	aging Alleles Animals bone Bone and Bones - metabolism Bone Marrow Cells - cytology Bone Remodeling bone strength CCN Intercellular Signaling Proteins - metabolism Cell Differentiation Cells, Cultured Extracellular Matrix - metabolism extracellular matrix protein Female Glycobiology and Extracellular Matrices Low Density Lipoprotein Receptor-Related Protein-1 Male Mice Mice, Knockout Osteoblasts - metabolism Osteoclasts - metabolism osteogenesis osteopenia Proto-Oncogene Proteins - metabolism Receptors, LDL - metabolism Recombination, Genetic RNA, Messenger - metabolism stromal cell Stromal Cells - cytology Tumor Suppressor Proteins - metabolism WISP1/CCN4 Wnt signaling Wnt Signaling Pathway X-Ray Microtomography stromal cell osteopenia extracellular matrix protein Wnt signaling WISP1/CCN4 bone aging osteogenesis bone strength
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Summary:	WISP1/CCN4 (hereafter referred to as WISP1), a member of the CCN family, is found in mineralized tissues and is produced by osteoblasts and their precursors. In this study, Wisp1-deficient (Wisp1−/−) mice were generated. Using dual-energy x-ray absorptiometry, we showed that by 3 months, the total bone mineral density of Wisp1−/− mice was significantly lower than that of WT mice. Further investigation by micro-computed tomography showed that female Wisp1−/− mice had decreased trabecular bone volume/total volume 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 with WT cells. Osteoclast precursors from Wisp1−/− mice developed more tartrate-resistant acid phosphatase-positive cells in vitro and in transplants, suggesting that WISP1 is also a negative regulator of osteoclast differentiation. When bone turnover (formation and resorption) was induced by ovariectomy, Wisp1−/− mice had lower bone mineral density compared WT mice, confirming the potential for multiple roles for WISP1 in controlling bone homeostasis. Wisp1−/− bone marrow stromal cells had reduced expression of β-catenin and its target genes, potentially caused by WISP1 inhibition of SOST binding to LRP6. Taken together, our data suggest that the decreased bone mass found in Wisp1−/− mice could potentially be caused by an insufficiency in the osteodifferentiation capacity of bone marrow stromal cells arising from diminished Wnt signaling, ultimately leading to altered bone turnover and weaker biomechanically compromised bones. Background: WISP1 is expressed in bone, but its roles in osteogenesis are unclear. Results: WISP1 regulates bone mineral content, cortical and trabecular bone thickness, and bone strength during aging by modulating osteoblast and osteoclast function and Wnt signaling. Conclusion: WISP1 controls bone integrity by regulating bone turnover. Significance: WISP1 is a novel target for modulating bone turnover and improving bone strength.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0021-9258 1083-351X
DOI:	10.1074/jbc.M114.628818