WNT1-Induced Secreted Protein-1 (WISP1), a novel regulator of bone turnover and Wnt signaling

Azusa Maeda, Mitsuaki Ono, Kenn Holmbeck, Li Li, Tina M. Kilts, Vardit Kram, Megan L. Noonan, Yuya Yoshioka, Erin M B McNerny, Margaret A. Tantillo, David H. Kohn, Karen M. Lyons, Pamela G. Robey, Marian F. Young

Research output: Contribution to journalArticle

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Abstract

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 Wisp-/- 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.

Original languageEnglish
Pages (from-to)14004-14018
Number of pages15
JournalJournal of Biological Chemistry
Volume290
Issue number22
DOIs
Publication statusPublished - May 29 2015

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Bone Remodeling
Bone
Proteins
Bone and Bones
Osteoclasts
Mesenchymal Stromal Cells
Osteogenesis
Bone Density
Minerals
Catenins
Ovariectomy
Bone Resorption
Osteoblasts
Transplants
Homeostasis
Acid Phosphatase
Tomography
X-Rays
Genes

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

WNT1-Induced Secreted Protein-1 (WISP1), a novel regulator of bone turnover and Wnt signaling. / 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.

In: Journal of Biological Chemistry, Vol. 290, No. 22, 29.05.2015, p. 14004-14018.

Research output: Contribution to journalArticle

Maeda, A, Ono, M, Holmbeck, K, Li, L, Kilts, TM, Kram, V, Noonan, ML, Yoshioka, Y, McNerny, EMB, Tantillo, MA, Kohn, DH, Lyons, KM, Robey, PG & Young, MF 2015, 'WNT1-Induced Secreted Protein-1 (WISP1), a novel regulator of bone turnover and Wnt signaling', Journal of Biological Chemistry, vol. 290, no. 22, pp. 14004-14018. https://doi.org/10.1074/jbc.M114.628818
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. / WNT1-Induced Secreted Protein-1 (WISP1), a novel regulator of bone turnover and Wnt signaling. In: Journal of Biological Chemistry. 2015 ; Vol. 290, No. 22. pp. 14004-14018.
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