Bone mass is inversely proportional to Dkk1 levels in mice.

Bone mass is inversely proportional to Dkk1 levels in mice. Research Abstract Details

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Bone mass is inversely proportional to Dkk1 levels in mice. Abstract Text:

Bryan T MacDonald,Danese M Joiner,Sivan M Oyserman,Parul Sharma,Steven A Goldstein,Xi He,Peter V Hauschka,

The Wnt/beta-catenin signaling pathway has emerged as a key regulator in bone development and bone homeostasis. Loss-of-function mutations in the Wnt co-receptor LRP5 result in osteoporosis and "activating" mutations in LRP5 result in high bone mass. Dickkopf-1 (DKK1) is a secreted Wnt inhibitor that binds LRP5 and LRP6 during embryonic development, therefore it is expected that a decrease in DKK1 will result in an increase in Wnt activity and a high bone mass phenotype. Dkk1-/- knockout mice are embryonic lethal, but mice with hypomorphic Dkk1d (doubleridge) alleles that express low amounts of Dkk1 are viable. In this study we generated an allelic series by crossing Dkk1+/- and Dkk1+/d mice resulting in the following genotypes with decreasing Dkk1 expression levels: +/+, +/d, +/- and d/-. Using muCT imaging we scanned dissected left femora and calvariae from 8-week-old mice (n=60). We analyzed the distal femur to represent trabecular bone and the femur diaphysis for cortical endochondral bone. A region of the parietal bones was used to analyze intramembranous bone of the calvaria. We found that trabecular bone volume is increased in Dkk1 mutant mice in a manner that is inversely proportional to the level of Dkk1 expression. Trabeculae number and thickness were significantly higher in the low Dkk1 expressing genotypes from both female and male mice. Similar results were found in cortical bone with an increase in cortical thickness and cross sectional area of the femur diaphysis that correlated with lower Dkk1 expression. No consistent differences were found in the calvaria measurements. Our results indicate that the progressive Dkk1 reduction increases trabecular and cortical bone mass and that even a 25% reduction in Dkk1 expression could produce significant increases in trabecular bone volume fraction. Thus DKK1 is a negative regulator of normal bone homeostasis in vivo. Our study suggests that manipulation of DKK1 function or expression may have therapeutic significance for the treatment of low bone mass disorders.

Bone mass is inversely proportional to Dkk1 levels in mice. Publishing Authors By Initials

BT MacDonald,DM Joiner,SM Oyserman,P Sharma,SA Goldstein,X He,PV Hauschka,

For similar tomography, x-ray computed research abstracts see: tomography, x-ray computed research

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Bone mass is inversely proportional to Dkk1 levels in mice. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Bone

VOLUME: 41

Page Numbers: 331-9

Journal Abbreviation: Bone

ISSN: 8756-3282

DAY: 5

MONTH: 06

YEAR: 2007

Bone mass is inversely proportional to Dkk1 levels in mice. Information

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LANGUAGE: eng

NlmUniqueID: 8504048

Bone mass is inversely proportional to Dkk1 levels in mice. Keywords Mesh Terms:

KEYWORDS: Tomography, X-Ray Computed

MESH TERMS: analysis

Chemical & Substance for Abstract: Bone mass is inversely proportional to Dkk1 levels in mice. Information

Substance Name: RNA, Messenger

Registry Number: 0

Grant and Affiliation Information for Bone mass is inversely proportional to Dkk1 levels in mice.

AFFILIATION: Division of Neuroscience, Department of Orthopedic Surgery, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. bryan.macdonald@childrens.harvard.edu

Country: United States