Knocking down dickkopf-1 alleviates estrogen deficiency induction of bone loss. A histomorphological study in ovariectomized rats

Wang, Feng‐Sheng; Ko, Jih‐Yang; Lin, Chun‐Liang; Wu, Hsing-Long; Ke, Huei-Ching; Tai, Pei-Ju

doi:10.1016/j.bone.2006.09.004

Cited by 93 publications

(51 citation statements)

References 40 publications

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“…[9][10][11][12][13][14] Our results show, for the first time, that Dkk1 is increased in the serum of thalassemia patients with osteoporosis. The correlation observed between serum Dkk1 and BMD of the R and L1-L4 as well as the independent value of Dkk1 in revealing the presence of severe osteoporosis further suggests that Dkk1 is implicated, at least partially, in the pathogenesis of osteoporosis in thalassemia.…”

Section: Resultssupporting

confidence: 50%

“…10 Dkk1 overexpression in osteoblasts causes osteopenia and inhibits fracture repair, 11 while Dkk1 activation in osteoblasts seems to participate in the pathogenesis of glucocorticoid-and estrogen deficiency-mediated osteoporosis. 12 Furthermore, Dkk1 is implicated in the pathogenesis of cancer related bone disease 11 and Dkk1 serum levels are elevated in patients with multiple myeloma and breast cancer with bone metastasis. 13,14 However, there is no information for the serum levels of Dkk1 in human osteoporosis of any benign etiology, including thalassemia-induced osteoporosis.…”

Section: Introductionmentioning

confidence: 99%

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Serum Dickkopf-1 is increased and correlates with reduced bone mineral density in patients with thalassemia-induced osteoporosis. Reduction post-zoledronic acid administration

Voskaridou¹,

Christoulas²,

Xirakia³

et al. 2009

Haematologica

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Terpos E. Serum Dickkopf-1 is increased and correlates with reduced bone mineral density in patients with thalassemiainduced osteoporosis. Reduction post-zoledronic acid administration. Haematologica 2009; 94:725-728. doi: 10.3324/haematol.2008 This is an open-access paper. ABSTRACTSerum Dickkopf-1 is increased and correlates with reduced bone mineral density in patients with thalassemia-induced osteoporosis. Reduction post-zoledronic acid administration Dkk1 was measured at baseline and after 12 months of therapy, using ELISA methodology (Biomedica Medizinprodukte, No. BI-20412, Gesellschaft GmbH, Wien, Austria; in this ELISA 1 pmol/L=28.68 pg/mL), along with a series of serum bone indices: i) bone resorption markers [C-telopeptide of type-I collagen (CTX), tartrate-resistant acid phosphatase isoform-5b (TRACP5b)], ii) bone formation markers [bone-alkaline phosphatase (bALP), osteocalcin (OC) and C-terminal propeptide of collagen type-I (CICP)], and iii) osteoclast regulators [receptor activator of nuclear factor-κB ligand (RANKL), osteoprotegerin (OPG), and osteopontin], as previously described. 4 Bone mineral density (BMD) of the lumbar spine (L1-L4), femoral neck (FN) and distal radius (R) was determined using Dual-Energy X-ray Absorptiometry (DXA; LUNAR, PRODIGY Version 8.60.006/SYSTEM GE medical system LUNAR USA 726, Heartland Trail, Madison, WI 53717, USA) before and 12 months post-ZOL treatment. 4 The above bone markers were also evaluated in 30, age-and gender-matched, healthy controls (11M/19F, median age 44 years, range: 21-55 years). All controls had BMD measurements (L1-L4/FN/R) to exclude osteopenia/osteoporosis of other etiology, and were examined to ensure that there was no evidence of bone disease (i.e. osteoarthritis) and no receipt of medication that could alter the normal bone turnover during the previous six months. Statistical analysisThe Mann-Whitney test and paired samples t-tests were applied to evaluate the differences between patients and controls while the Wilcoxon signed rank test was used to evaluate differences between baseline and values of the studied parameters at the various time points. Differences between patients of three groups were evaluated using the Mann-Whitney test and the one-way ANOVA. The correlation between changes of various biochemical parameters and BMD was evaluated with the Spearman's (rs) correlation coefficient. Variables found to be statistically significant at the p<0.05 level for the presence of severe osteoporosis (Z-score< -4.0) in at least one studied site were entered into a multivariate model using Cox regression analysis to identify the most statistically significant model. All p values are two sided, the level of significance is <0.05 and confidence intervals refer to 95% boundaries. © F e r r a t a S t o r t i F o u n d a t i o n Results and DiscussionAt baseline, thalassemia patients had increased serum levels of Dkk1 (mean±SD: 39±17.1 pmol/L) compared with controls (27.4±9.7 pmol/L; p<0.0001; Figure 1A Figure 1B) and R-BMD (r=-0.415, p=0.001...

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Section: Resultssupporting

confidence: 50%

Section: Introductionmentioning

confidence: 99%

Serum Dickkopf-1 is increased and correlates with reduced bone mineral density in patients with thalassemia-induced osteoporosis. Reduction post-zoledronic acid administration

Voskaridou¹,

Christoulas²,

Xirakia³

et al. 2009

Haematologica

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“…Dkk1 antibodies enhance endochondral bone healing in LRP5 deficient mice [16]. Inhibition of Dkk1 can counter some of the effects of oestrogen deficiency in rats, restoring bone mineral content and density [35]. Blocking of other Wnt-inhibitors could also influence bone formation: mice deficient in secreted frizzled related protein 1 (sFRP1) have higher bone mass and faster healing of diaphyseal fractures [36].…”

Section: Discussionmentioning

confidence: 99%

The effects of Dickkopf-1 antibody on metaphyseal bone and implant fixation under different loading conditions

Agholme

Isaksson

Kuhstoss

et al. 2011

Bone

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The secreted protein Dickkopf-1 (Dkk1) is an antagonist of canonical Wnt signaling, expressed during fracture healing. It is unknown if it is involved in the mechanical control of bone maintenance. We investigated the response to administration of a Dkk1 neutralizing antibody (Dkk1-ab) in metaphyseal bone under different loading conditions, with or without trauma. In this three part experiment, 120 rats had a screw or bone chamber inserted either unilaterally or bilaterally in the proximal tibia. Mechanical (pull-out) testing, µCT and histology were used for evaluation. The animals were injected with either 10 mg/kg Dkk1-ab or saline every 14 days for 14, 28, or 42 days. Antibody treatment increased bone formation around the screws and improved their fixation. After 28 days, the pull-out force was increased by over 100%. In cancellous bone, the bone volume fraction was increased by 50%. In some animals, one hind limb was paralyzed with Botullinum toxin A (Botox) to create a mechanically unloaded environment. This did not increase the response to antibody treatment with regard to screw fixation, but in cancellous bone, the bone volume fraction increased by 233 %. Thus, the response in unloaded, untraumatized bone was proportionally larger, suggesting that Dkk1 may be up-regulated in unloaded bone. There was also an increase in thickness of the metaphyseal cortex. In bone chambers, the antibody treatment increased the bone volume fraction. The results suggest that antibodies blocking Dkk1 might be used to stimulate bone formation especially during implant fixation, fracture repair, or bone disuse. It also seems that Dkk1 is up-regulated both after metaphyseal trauma and after unloading, and that Dkk1 is involved in mechano-transduction.

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“…44 Genetic data regarding the effects of DKK1 on bone mass are supported by experiments where ovariectomized or sham-operated rats were given 20 g/kg per day Dkk1 sense or antisense oligonucleotide or vehicle for 28 days, and it was noted that Dkk1 antisense oligonucleotide significantly abrogated the suppressive effect of ovariectomy (ie, estrogen deficiency) on femur weight, mineral content, mineral density, and peak load. 45 In contrast, dexamethasone, an agent known to induce osteoporosis, upregulates Dkk1 expression in primary human osteoblasts and may provide a molecular explanation for osteoporosis caused by long-term glucocorticoid use. 46 Moreover, knockdown of Dkk1 expression by antisense oligonucleotide (Dkk1-AS) abrogated dexamethasone suppression of alkaline phosphatase activity and osteocalcin expression in MC3T3-E1 preosteoblasts, and mitigated dexamethasone-mediated suppression of mineral density, trabecular bone volume, osteoblast surface, and bone formation rate in bone tissue and ex vivo osteogenesis of primary bone marrow mesenchymal cells.…”

Section: Overview Of Wnt Signalingmentioning

confidence: 99%

The role of Dickkopf-1 in bone development, homeostasis, and disease

Pinzone¹,

Hall

Thudi

et al. 2009

Blood

361

271

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Overview of Wnt signalingThe Wnt family of glycoproteins signals through a "canonical" or "noncanonical" pathway ( Figure 1). In the absence of Wnt's, glycogen synthase kinase-␤ (GSK3␤), Axin, adenomatous polyposis coli (APC), and casein kinase I␣ (CKI␣) form a ␤-catenin destruction complex. 1 CKI␣ phosphorylates ␤-catenin at Ser45, and then GSK3␤ phosphorylates ␤-catenin at Ser33/Ser37/Thr41. Phosphorylated ␤-catenin is recognized by ␤-transducin repeat protein, ubiquitinated, and degraded by proteasomes. In contrast, activation of canonical Wnt signaling occurs when a Wnt protein binds to one of the 10 members of the frizzled (FZD) receptor family; Wnt-FZD then binds low-density lipoprotein-related protein-5 (LRP5) or LRP6. The resultant complex activates Dishevelled (Dvl), a protein that attracts Axin away from the destruction complex and antagonizes the ability of GSK3␤ to phosphorylate ␤-catenin, thereby preventing destruction complex formation. If ␤-catenin is not degraded, it translocates to the nucleus where it binds to the transcription factor T-cell factor-4 (TCF4) and enhances target gene expression. 1 Canonical Wnt's promote caveolin-dependent LRP internalization and facilitate its interaction with Axin. 2 In contrast, DKK1 binds to LRP5/6 causing the receptor to attract a Kremen; this interaction promotes clathrin-mediated internalization, thereby inactivating LRP, though some data suggest that Kremen may not be essential for DKK1-mediated Wnt inhibition. 3,4 Moreover, R-Spondins amplify the activity of canonical Wnt's while antagonizing DKK1-mediated interaction with LRP and Kremen. 5 Wise and SOST are also secreted Wnt inhibitors that bind to and inactivate LRP. 6,7 Wnt inhibitory factor (WIF) proteins, which are structurally similar to the extracellular portion of the Derailed/Ryk class of transmembrane Wnt receptors, and secreted forms of frizzled proteins (sFRP, sizzled, and FrzB) act by directly binding Wnt molecules and can function as Wnt inhibitors, but may also stabilize Wnt's and facilitate Wnt signaling. 8,9 DKK1 regulates bone development and accrual and maintenance of bone mass Bone marrow-derived mesenchymal stem cells (MSC) can differentiate into adipocytes, chondrocytes, or osteoblasts. Although the precise orchestration of Wnt signaling during bone development is dependent on complex microenvironmental cues, data from several groups suggest that Wnt3a, Wnt5a, Wnt7b, and Wnt10b are central to osteoblast differentiation (Figure 2). 10-14 Increased ␤-catenin is found in cells committed to the osteoblast lineage, and loss of ␤-catenin in osteoblast precursor cells results in reduced bone deposition. 15 In addition to promoting osteoblast commitment, canonical Wnt signaling inhibits adipocyte differentiation, primarily through accrual of stabilized ␤-catenin and subsequent transactivation of TCF-responsive genes. 16,17 However, noncanonical Wnt signaling through Wnt5a inactivates peroxisome proliferatoractivated receptor-␥ (PPAR␥), a key adipogenic transcription factor and activates Ru...

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Knocking down dickkopf-1 alleviates estrogen deficiency induction of bone loss. A histomorphological study in ovariectomized rats

Cited by 93 publications

References 40 publications

Serum Dickkopf-1 is increased and correlates with reduced bone mineral density in patients with thalassemia-induced osteoporosis. Reduction post-zoledronic acid administration

Serum Dickkopf-1 is increased and correlates with reduced bone mineral density in patients with thalassemia-induced osteoporosis. Reduction post-zoledronic acid administration

The effects of Dickkopf-1 antibody on metaphyseal bone and implant fixation under different loading conditions

The role of Dickkopf-1 in bone development, homeostasis, and disease

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