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Updated: Jul 13, 2026
Trabecular Bone Microarchitecture Evaluation in an Osteoporosis Mouse Model
Published on: September 8, 2023
Bone mass is inversely proportional to Dkk1 levels in mice
Bryan T MacDonald1, Danese M Joiner, Sivan M Oyserman
1Division of Neuroscience, Department of Orthopedic Surgery, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. bryan.macdonald@childrens.harvard.edu
Abstract:
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.
Insights
Reducing Dickkopf-1 (DKK1) levels increases bone mass. Lowering DKK1 expression in mice significantly enhanced trabecular and cortical bone, suggesting DKK1 as a therapeutic target for bone disorders.
Area of Science:
- Bone Biology and Skeletal Homeostasis
- Signaling Pathways in Development
- Wnt Signaling Pathway Regulation
Background:
- The Wnt/beta-catenin pathway is crucial for bone development and homeostasis.
- Mutations in LRP5 cause osteoporosis or high bone mass.
- Dickkopf-1 (DKK1) inhibits Wnt signaling by binding LRP5/LRP6.
Purpose of the Study:
- To investigate the in vivo effect of reduced Dickkopf-1 (DKK1) expression on bone mass.
- To determine the relationship between DKK1 levels and bone density.
- To assess DKK1's role as a regulator of bone homeostasis.
Main Methods:
- Generated an allelic series of mice with varying Dkk1 expression levels.
- Utilized micro-computed tomography (muCT) imaging to analyze bone structure.
- Examined trabecular bone (distal femur) and cortical bone (femur diaphysis).
Main Results:
- Progressive reduction in Dkk1 expression inversely correlated with increased trabecular bone volume.
- Lower Dkk1 levels led to significantly higher trabeculae number and thickness.
- Cortical bone showed increased thickness and cross-sectional area with reduced Dkk1.
Conclusions:
- Dickkopf-1 (DKK1) acts as a negative regulator of bone mass in vivo.
- Even a 25% reduction in DKK1 significantly increases trabecular bone volume.
- Modulating DKK1 offers potential therapeutic strategies for low bone mass disorders.
