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

doi:10.1074/jbc.m114.628818

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

44 Citations (Scopus)

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 language	English
Journal	The Journal of Biological Chemistry
Volume	290
Issue number	22
Pages (from-to)	14004-14018
Number of pages	15
ISSN	0021-9258
DOIs	https://doi.org/10.1074/jbc.m114.628818
Publication status	Published - 29 May 2015
Externally published	Yes

Keywords

Alleles
Animals
Bone Marrow Cells/cytology
Bone Remodeling
Bone and Bones/metabolism
CCN Intercellular Signaling Proteins/metabolism
Cell Differentiation
Cells, Cultured
Extracellular Matrix/metabolism
Female
Male
Mice
Mice, Knockout
Osteoblasts/metabolism
Osteoclasts/metabolism
Proto-Oncogene Proteins/metabolism
RNA, Messenger/metabolism
Receptors, LDL/metabolism
Recombination, Genetic
Stromal Cells/cytology
Tumor Suppressor Proteins/metabolism
Wnt Signaling Pathway
X-Ray Microtomography

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10.1074/jbc.m114.628818

http://www.jbc.org/content/290/22/14004.full.pdfLicence: CC BY

Cite this

Maeda, A., Ono, M., Holmbeck, K., Li, L., Kilts, T. M., Kram, V., Noonan, M. L., Yoshioka, Y., McNerny, E. M. B., Tantillo, M. A., Kohn, D. H., Lyons, K. M., Robey, P. G., & Young, M. F. (2015). WNT1-induced Secreted Protein-1 (WISP1), a Novel Regulator of Bone Turnover and Wnt Signaling. The Journal of Biological Chemistry, 290(22), 14004-14018. https://doi.org/10.1074/jbc.m114.628818

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

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.",

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

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doi = "10.1074/jbc.m114.628818",

language = "English",

volume = "290",

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journal = "The Journal of Biological Chemistry",

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T1 - WNT1-induced Secreted Protein-1 (WISP1), a Novel Regulator of Bone Turnover and Wnt Signaling

AU - Maeda, Azusa

AU - Ono, Mitsuaki

AU - Holmbeck, Kenn

AU - Li, Li

AU - Kilts, Tina M

AU - Kram, Vardit

AU - Noonan, Megan L.

AU - Yoshioka, Yuya

AU - McNerny, Erin M. B.

AU - Tantillo, Margaret A.

AU - Kohn, David H.

AU - Lyons, Karen M.

AU - Robey, Pamela G.

AU - Young, Marian F

PY - 2015/5/29

Y1 - 2015/5/29

N2 - 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.

AB - 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.

KW - Alleles

KW - Animals

KW - Bone Marrow Cells/cytology

KW - Bone Remodeling

KW - Bone and Bones/metabolism

KW - CCN Intercellular Signaling Proteins/metabolism

KW - Cell Differentiation

KW - Cells, Cultured

KW - Extracellular Matrix/metabolism

KW - Female

KW - Male

KW - Mice

KW - Mice, Knockout

KW - Osteoblasts/metabolism

KW - Osteoclasts/metabolism

KW - Proto-Oncogene Proteins/metabolism

KW - RNA, Messenger/metabolism

KW - Receptors, LDL/metabolism

KW - Recombination, Genetic

KW - Stromal Cells/cytology

KW - Tumor Suppressor Proteins/metabolism

KW - Wnt Signaling Pathway

KW - X-Ray Microtomography

U2 - 10.1074/jbc.m114.628818

DO - 10.1074/jbc.m114.628818

M3 - Journal article

C2 - 25864198

SN - 0021-9258

VL - 290

SP - 14004

EP - 14018

JO - The Journal of Biological Chemistry

JF - The Journal of Biological Chemistry

IS - 22

ER -

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

Abstract

Keywords

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