Bone Mass and Strength are Significantly Improved in Mice Overexpressing Human WNT16 in Osteocytes

被引：20

作者：

Alam, Imranul ^{[1
]}

Reilly, Austin M. ^{[1
]}

Alkhouli, Mohammed ^{[1
]}

Gerard-O'Riley, Rita L. ^{[1
]}

Kasipathi, Charishma ^{[1
]}

Oakes, Dana K. ^{[1
]}

Wright, Weston B. ^{[1
]}

Acton, Dena ^{[1
]}

McQueen, Amie K. ^{[1
]}

Patel, Bhavmik ^{[1
]}

Lim, Kyung-Eun ^{[3
]}

Robling, Alexander G. ^{[3
]}

Econs, Michael J. ^{[1
,2
]}

机构：

[1] Indiana Univ Sch Med, Div Endocrinol, Dept Med, 1120 West Michigan St,CL459, Indianapolis, IN 46202 USA

[2] Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA

[3] Indiana Univ Sch Med, Dept Anat & Cell Biol, Indianapolis, IN 46202 USA

来源：

CALCIFIED TISSUE INTERNATIONAL | 2017年 / 100卷 / 04期

基金：

美国国家卫生研究院;

关键词：

WNT16; Osteocyte; Transgenic; Bone mass; Gene; Osteoporosis; GENOME-WIDE; MINERAL DENSITY; METAANALYSIS; OSTEOPOROSIS; DISEASE; FRACTURES; LOCI;

D O I：

10.1007/s00223-016-0225-4

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Recently, we demonstrated that osteoblast-specific overexpression of human WNT16 increased both cortical and trabecular bone mass and structure in mice. To further identify the cell-specific role of Wnt16 in bone homeostasis, we created transgenic (TG) mice overexpressing human WNT16 in osteocytes using Dmp1 promoter (Dmp1-hWNT16 TG) on C57BL/6 (B6) background. We analyzed bone phenotypes and serum bone biomarkers, performed gene expression analysis and measured dynamic bone histomorphometry in Dmp1-hWNT16 TG and wild-type (WT) mice. Compared to WT mice, Dmp1-hWNT16 TG mice exhibited significantly higher whole-body, spine and femoral aBMD, BMC and trabecular (BV/TV, Tb.N, and Tb.Th) and cortical (bone area and thickness) parameters in both male and female at 12 weeks of age. Femur stiffness and ultimate force were also significantly improved in the Dmp1-hWNT16 TG female mice, compared to sex-matched WT littermates. In addition, female Dmp1-hWNT16 TG mice displayed significantly higher MS/BS, MAR and BFR/BS compared to the WT mice. Gene expression analysis demonstrated significantly higher mRNA level of Alp in both male and female Dmp1-hWNT16 TG mice and significantly higher levels of Osteocalcin, Opg and Rankl in the male Dmp1-hWNT16 TG mice in bone tissue compared to sex-matched WT mice. These results indicate that WNT16 plays a critical role for acquisition of both cortical and trabecular bone mass and strength. Strategies designed to use WNT16 as a target for therapeutic interventions will be valuable to treat osteoporosis and other low bone mass conditions.

引用

页码：361 / 373

页数：13

共 21 条

[1] Osteoblast-Specific Overexpression of Human WNT16 Increases Both Cortical and Trabecular Bone Mass and Structure in Mice [J].

Alam, Imranul ;

Alkhouli, Mohammed ;

Gerard-O'Riley, Rita L. ;

Wright, Weston B. ;

Acton, Dena ;

Gray, Amie K. ;

Patel, Bhavmik ;

Reilly, Austin M. ;

Lim, Kyung-Eun ;

Robling, Alexander G. ;

Econs, Michael J. .

ENDOCRINOLOGY, 2016, 157 (02) :722-736

[2] WNT signaling in bone homeostasis and disease: from human mutations to treatments [J].

Baron, Roland ;

Kneissel, Michaela .

NATURE MEDICINE, 2013, 19 (02) :179-192

[3] Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture [J].

Berndt, Sonja I. ;

Gustafsson, Stefan ;

Maegi, Reedik ;

Ganna, Andrea ;

Wheeler, Eleanor ;

Feitosa, Mary F. ;

Justice, Anne E. ;

Monda, Keri L. ;

Croteau-Chonka, Damien C. ;

Day, Felix R. ;

Esko, Tonu ;

Fall, Tove ;

Ferreira, Teresa ;

Gentilini, Davide ;

Jackson, Anne U. ;

Luan, Jian'an ;

Randall, Joshua C. ;

Vedantam, Sailaja ;

Willer, Cristen J. ;

Winkler, Thomas W. ;

Wood, Andrew R. ;

Workalemahu, Tsegaselassie ;

Hu, Yi-Juan ;

Lee, Sang Hong ;

Liang, Liming ;

Lin, Dan-Yu ;

Min, Josine L. ;

Neale, Benjamin M. ;

Thorleifsson, Gudmar ;

Yang, Jian ;

Albrecht, Eva ;

Amin, Najaf ;

Bragg-Gresham, Jennifer L. ;

Cadby, Gemma ;

den Heijer, Martin ;

Eklund, Niina ;

Fischer, Krista ;

Goel, Anuj ;

Hottenga, Jouke-Jan ;

Huffman, Jennifer E. ;

Jarick, Ivonne ;

Johansson, Asa ;

Johnson, Toby ;

Kanoni, Stavroula ;

Kleber, Marcus E. ;

Koenig, Inke R. ;

Kristiansson, Kati ;

Kutalik, Zoltn ;

Lamina, Claudia ;

Lecoeur, Cecile .

NATURE GENETICS, 2013, 45 (05) :501-U69

[4] Wnt Signaling from Development to Disease: Insights from Model Systems [J].

Cadigan, Ken M. ;

Peifer, Mark .

COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY, 2009, 1 (02) :a002881

[5] Wnt/β-Catenin Signaling and Disease [J].

Clevers, Hans ;

Nusse, Roel .

CELL, 2012, 149 (06) :1192-1205

[6] Standardized Nomenclature, Symbols, and Units for Bone Histomorphometry: A 2012 Update of the Report of the ASBMR Histomorphometry Nomenclature Committee [J].

Dempster, David W. ;

Compston, Juliet E. ;

Drezner, Marc K. ;

Glorieux, Francis H. ;

Kanis, John A. ;

Malluche, Hartmut ;

Meunier, Pierre J. ;

Ott, Susan M. ;

Recker, Robert R. ;

Parfitt, A. Michael .

JOURNAL OF BONE AND MINERAL RESEARCH, 2013, 28 (01) :1-16

[7] Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture [J].

Estrada, Karol ;

Styrkarsdottir, Unnur ;

Evangelou, Evangelos ;

Hsu, Yi-Hsiang ;

Duncan, Emma L. ;

Ntzani, Evangelia E. ;

Oei, Ling ;

Albagha, Omar M. E. ;

Amin, Najaf ;

Kemp, John P. ;

Koller, Daniel L. ;

Li, Guo ;

Liu, Ching-Ti ;

Minster, Ryan L. ;

Moayyeri, Alireza ;

Vandenput, Liesbeth ;

Willner, Dana ;

Xiao, Su-Mei ;

Yerges-Armstrong, Laura M. ;

Zheng, Hou-Feng ;

Alonso, Nerea ;

Eriksson, Joel ;

Kammerer, Candace M. ;

Kaptoge, Stephen K. ;

Leo, Paul J. ;

Thorleifsson, Gudmar ;

Wilson, Scott G. ;

Wilson, James F. ;

Aalto, Ville ;

Alen, Markku ;

Aragaki, Aaron K. ;

Aspelund, Thor ;

Center, Jacqueline R. ;

Dailiana, Zoe ;

Duggan, David J. ;

Garcia, Melissa ;

Garcia-Giralt, Natalia ;

Giroux, Sylvie ;

Hallmans, Goran ;

Hocking, Lynne J. ;

Husted, Lise Bjerre ;

Jameson, Karen A. ;

Khusainova, Rita ;

Kim, Ghi Su ;

Kooperberg, Charles ;

Koromila, Theodora ;

Kruk, Marcin ;

Laaksonen, Marika ;

Lacroix, Andrea Z. ;

Lee, Seung Hun .

NATURE GENETICS, 2012, 44 (05) :491-+

[8] Missense polymorphisms of the WNT16 gene are associated with bone mass, hip geometry and fractures [J].

Garcia-Ibarbia, C. ;

Perez-Nunez, M. I. ;

Olmos, J. M. ;

Valero, C. ;

Perez-Aguilar, M. D. ;

Hernandez, J. L. ;

Zarrabeitia, M. T. ;

Gonzalez-Macias, J. ;

Riancho, J. A. .

OSTEOPOROSIS INTERNATIONAL, 2013, 24 (09) :2449-2454

[9] Variation in the Kozak sequence of WNT16 results in an increased translation and is associated with osteoporosis related parameters [J].

Hendrickx, Gretl ;

Boudin, Eveline ;

Fijalkowski, Igor ;

Nielsen, Torben Leo ;

Andersen, Marianne ;

Brixen, Kim ;

Van Hul, Wim .

BONE, 2014, 59 :57-65

[10] Phenotypic Dissection of Bone Mineral Density Reveals Skeletal Site Specificity and Facilitates the Identification of Novel Loci in the Genetic Regulation of Bone Mass Attainment [J].

Kemp, John P. ;

Medina-Gomez, Carolina ;

Estrada, Karol ;

St Pourcain, Beate ;

Heppe, Denise H. M. ;

Warrington, Nicole M. ;

Oei, Ling ;

Ring, Susan M. ;

Kruithof, Claudia J. ;

Timpson, Nicholas J. ;

Wolber, Lisa E. ;

Reppe, Sjur ;

Gautvik, Kaare ;

Grundberg, Elin ;

Ge, Bing ;

van der Eerden, Bram ;

van de Peppel, Jeroen ;

Hibbs, Matthew A. ;

Ackert-Bicknell, Cheryl L. ;

Choi, Kwangbom ;

Koller, Daniel L. ;

Econs, Michael J. ;

Williams, Frances M. K. ;

Foroud, Tatiana ;

Zillikens, M. Carola ;

Ohlsson, Claes ;

Hofman, Albert ;

Uitterlinden, Andre G. ;

Smith, George Davey ;

Jaddoe, Vincent W. V. ;

Tobias, Jonathan H. ;

Rivadeneira, Fernando ;

Evans, David M. .

PLOS GENETICS, 2014, 10 (06)

← 1 2 3 →