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

Pinzone, Joseph J.; Hall, Brett M.; Thudi, Nanda K.; Vonau, Martin; Qiang, Ya‐Wei; Rosol, Thomas J.; Shaughnessy, John D.

doi:10.1182/blood-2008-03-145169

Cited by 361 publications

(295 citation statements)

References 101 publications

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“…Dkk-1 is expressed in many tissues during embryogenesis, including bone (14). Aberrant expression of Dkk-1 has been found in diseases that impair bone health, such as multiple myeloma (15).…”

Section: Introductionmentioning

confidence: 99%

Sclerostin and Dickkopf-1 in Renal Osteodystrophy

Cejka¹,

Herberth²,

Branscum³

et al. 2011

Clinical Journal of the American Society of Nephrology

223

176

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SummaryBackground and objectives The serum proteins sclerostin and Dickkopf-1 (Dkk-1) are soluble inhibitors of canonical wnt signaling and were recently identified as components of parathyroid hormone (PTH) signal transduction. This study investigated the associations between sclerostin and Dkk-1 with histomorphometric parameters of bone turnover, mineralization, and volume in stage 5 chronic kidney disease patients on dialysis (CKD-5D). Design, setting, participants, & measurementsIn a cross-sectional study, 60 CKD-5D patients underwent bone biopsies followed by histomorphometry. Levels of sclerostin, Dkk-1, and intact PTH (iPTH) were determined in blood.Results Serum levels of sclerostin and iPTH correlated negatively. In unadjusted analyses, sclerostin correlated negatively with histomorphometric parameters of turnover, osteoblastic number, and function. In adjusted analyses, sclerostin remained a strong predictor of parameters of bone turnover and osteoblast number. An observed correlation between sclerostin and cancellous bone volume was lost in regression analyses. Sclerostin was superior to iPTH for the positive prediction of high bone turnover and number of osteoblasts. In contrast, iPTH was superior to sclerostin for the negative prediction for high bone turnover and had similar predictive values than sclerostin for the number of osteoblasts. Serum levels of Dkk-1 did not correlate with iPTH or with any histomorphometric parameter.Conclusions Our data describe a promising role for serum measurements of sclerostin in addition to iPTH in the diagnosis of high bone turnover in CKD-5D patients, whereas measurements of Dkk-1 do not seem to be useful for this purpose.

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Section: Introductionmentioning

confidence: 99%

Sclerostin and Dickkopf-1 in Renal Osteodystrophy

Cejka¹,

Herberth²,

Branscum³

et al. 2011

Clinical Journal of the American Society of Nephrology

223

176

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“…Some Wnt proteins such as Wnt3a and Wnt10b bind to Frizzled receptors, and recruit the LRP5/6 coreceptors to activate the canonical signaling pathway, leading to glycogen synthase kinase-b (GSK3b) inhibition, b-catenin stabilization, translocation into the nucleus and regulation of TCF/LEF transcriptional activity. Binding of Wnt proteins to LRP5/6 is inhibited by secreted factors such as Dickkopf1 (Dkk1) [14]. Dkk1 binds to LRP5/6 causing the receptor to attract Kremen, and this interaction promotes clathrin-mediated internalization thereby inactivating LRP5/6.…”

Section: Introductionmentioning

confidence: 99%

Autocrine stimulation of osteoblast activity by Wnt5a in response to TNF-α in human mesenchymal stem cells

Briolay

Lencel²,

Bessueille

et al. 2013

Biochemical and Biophysical Research Communications

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a b s t r a c tAlthough anti-tumor necrosis factor (TNF)-a treatments efficiently block inflammation in ankylosing spondylitis (AS), they are inefficient to prevent excessive bone formation. In AS, ossification seems more prone to develop in sites where inflammation has resolved following anti-TNF therapy, suggesting that TNF-a indirectly stimulates ossification. In this context, our objectives were to determine and compare the involvement of Wnt proteins, which are potent growth factors of bone formation, in the effects of TNF-a on osteoblast function. In human mesenchymal stem cells (MSCs), TNF-a significantly increased the levels of Wnt10b and Wnt5a. Associated with this effect, TNF-a stimulated tissue-non specific alkaline phosphatase (TNAP) and mineralization. This effect was mimicked by activation of the canonical bcatenin pathway with either anti-Dkk1 antibodies, lithium chloride (LiCl) or SB216763. TNF-a reduced, and activation of b-catenin had little effect on expression of osteocalcin, a late marker of osteoblast differentiation. Surprisingly, TNF-a failed to stabilize b-catenin and Dkk1 did not inhibit TNF-a effects. In fact, Dkk1 expression was also enhanced in response to TNF-a, perhaps explaining why canonical signaling by Wnt10b was not activated by TNF-a. However, we found that Wnt5a also stimulated TNAP in MSCs cultured in osteogenic conditions, and increased the levels of inflammatory markers such as COX-2. Interestingly, treatment with anti-Wnt5a antibodies reduced endogenous TNAP expression and activity. Collectively, these data suggest that increased levels of Dkk1 may blunt the autocrine effects of Wnt10b, but not that of Wnt5a, acting through non-canonical signaling. Thus, Wnt5a may be potentially involved in the effects of inflammation on bone formation.

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“…The following biochemical parameters were measured because of their novelty or correlation with bone parameters in cross-sectional prior studies: serum parathyroid hormone (PTH; commonly used to assess bone turnover abnormalities, which have been shown to be associated with changes in bone volume) (12), bone-specific alkaline phosphatase (BSAP) and procollagen type 1 N-terminal propeptide (P1NP; which are markers of osteoblastic activity) (13,14), tartrate-resistant acid phosphatase-5b (TRAP-5b; a marker of osteoclastic activity) (15), sclerostin (a protein produced by osteocytes [16,17] and expressed at bone formation sites [18,19]), Dickkopf-1 (DKK-1; found in bone and other tissues [20], and like sclerostin, it leads to increased bone formation and bone volume when knocked out) (21,22), and fibroblast growth factor 23 (FGF23; involved in mineral metabolism with a role in bone mineralization/remodeling) (23)(24)(25). In addition, serum calcium and phosphorus were measured.…”

Section: Determinations Of Blood Parametersmentioning

confidence: 99%

Bone Mineral Density and Serum Biochemical Predictors of Bone Loss in Patients with CKD on Dialysis

Malluche¹,

Davenport

Cantor³

et al. 2014

Clinical Journal of the American Society of Nephrology

122

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Background and objectives Use of bone mineral density (BMD) by dual-energy x-ray absorptiometry (DXA) is controversial for diagnosing bone loss in CKD patients on dialysis. The alternative quantitative computed tomography (QCT) is expensive and requires high radiation exposure. This study compared the two techniques and evaluated serum biochemical parameters for prediction of bone loss.Design, setting, participants, & measurements This prospective study enrolled patients from dialysis centers throughout Kentucky. BMD of the spine and hip was measured at baseline and after 1 year by DXA and QCT. Customary and novel serum biochemical parameters were obtained at the same times, including calcium, phosphorus, whole and intact parathyroid hormone, bone-specific alkaline phosphatase, procollagen type 1 N-terminal propeptide, tartrate-resistant acid phosphatase-5b, Dickkopf-1, fibroblast growth factor, and sclerostin. Rates of detection of osteoporosis by DXA and QCT were compared. Correlations were calculated between baseline biochemical parameters and BMD at baseline and changes over 1 year. Multivariable regression was performed to adjust for age, sex, body mass index, and race.Results Eighty-one patients completed the study (mean age=52.6612.3 years, 56% men, 53% African American, and median dialysis vintage=41 months). At baseline, QCT and DXA of the spine identified similar rates of osteoporosis (13.6% and 13.6%), but at the hip, DXA identified more osteoporosis (22.2% versus 13.6%). At any site and by either method, 33.3% of the patients were osteoporotic. Baseline BMD correlated with sclerostin, intact parathyroid hormone, bone-specific alkaline phosphatase, tartrate-resistant acid phosphatase-5b, and fibroblast growth factor. At 1 year, hip QCT identified a higher number of patients experiencing bone loss (51.3%) than DXA (38.5%). After multivariable adjustment, baseline sclerostin and tartrate-resistant acid phosphatase-5b predicted bone loss measured by QCT of the hip; procollagen type 1 N-terminal propeptide predicted cortical spine bone gain by QCT.Conclusions QCT identified prospectively more bone loss at the hip than DXA. The baseline serum biochemical parameters sclerostin and tartrate-resistant acid phosphatase-5b were noninvasive independent predictors of bone loss in CKD patients on dialysis.

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

Cited by 361 publications

References 101 publications

Sclerostin and Dickkopf-1 in Renal Osteodystrophy

Sclerostin and Dickkopf-1 in Renal Osteodystrophy

Autocrine stimulation of osteoblast activity by Wnt5a in response to TNF-α in human mesenchymal stem cells

Bone Mineral Density and Serum Biochemical Predictors of Bone Loss in Patients with CKD on Dialysis

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