Article

Bone mass is inversely proportional to Dkk1 levels in mice

Division of Neuroscience, Department of Orthopedic Surgery, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Bone (Impact Factor: 4.46). 10/2007; 41(3):331-9. DOI: 10.1016/j.bone.2007.05.009
Source: PubMed

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.

Full-text

Available from: Bryan T Macdonald, May 26, 2015
0 Followers
 · 
99 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Dickkopf-1 (DKK-1) has been proved dysfunctional in ankylosing spondylitis (AS), and decreased serum functional DKK-1 levels have been identified to be decreased in AS patients. This study aims to examine the relation of binding (functional) DKK-1 levels in serum with the radiographic severity of AS. Methods: Total Dkk1 levels were assessed by commercial sandwich enzyme-linked immunosorbent assay and functional DKK-1 levels of serum were measured using functional enzyme-linked immunosorbent assay method in 84 patients with AS and 79 healthy controls. The radiographic progression of AS was classified according to the radiographic events of modified New York Criteria for sacroiliac joints evaluation and modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) system for spine assessment. Results: No significant difference was seen between AS patients and healthy controls for total Dkk1 levels (p = 0.273). Decreased levels of functional DKK-1 in serum were found in AS patients compared with healthy controls [7.24 (1.24 - 11.15) vs. 9.15 (5.33 - 13.35) pg/mL, p < 0.001]. Functional DKK-1 levels in serum of AS patients were significantly associated with the disease radiographic severity evaluated by modified New York grading criteria (r = -0.236, p = 0.04) and mSASSS system (r = -0.389, p = 0.025). Conclusions: Serum functional DKK-1 levels showed an independent and negative correlation with radiographic severity of the disease in patients with AS. Functional DKK-1 in serum might serve as a potential biomarker for reflecting the progression of ankylosing spondylitis.
    Clinical laboratory 01/2014; 60(9):1527-31. DOI:10.7754/Clin.Lab.2014.131119 · 1.08 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In this study we investigated if Wnt/β-catenin signaling in mesenchymal progenitor cells plays a role in bone fracture repair and if DKK1-Ab promotes fracture healing through activation of β-catenin signaling. Unilateral open transverse tibial fractures were created in CD1 mice and in β-catenin(Prx1ER) conditional knockout (KO) and Cre-negative control mice (C57BL/6 background). Bone fracture callus tissues were collected and analyzed by radiography, micro-CT (μCT), histology, biomechanical testing and gene expression analysis. The results demonstrated that treatment with DKK1-Ab promoted bone callus formation and increased mechanical strength during the fracture healing process in CD1 mice. DKK1-Ab enhanced fracture repair by activation of endochondral ossification. The normal rate of bone repair was delayed when the β-catenin gene was conditionally deleted in mesenchymal progenitor cells during the early stages of fracture healing. DKK1-Ab appeared to act through β-catenin signaling to enhance bone repair since the beneficial effect of DKK1-Ab was abrogated in β-catenin(Prx1ER) conditional KO mice. Further understanding of the signaling mechanism of DKK1-Ab in bone formation and bone regeneration may facilitate the clinical translation of this anabolic agent into therapeutic intervention.
    Bone 09/2014; 71. DOI:10.1016/j.bone.2014.07.039 · 4.46 Impact Factor
  • Source