Suppression of Wnt Signaling by Dkk1 Attenuates PTH-Mediated Stromal Cell Response and New Bone Formation

Guo, Jun; Liu, Minlin; Yang, Dehong; Bouxsein, Mary L.; Saito, Hiroaki; Galvin, Rachelle J. Sells; Kuhstoss, Stuart; Thomas, Clare C.; Schipani, Ernestina; Baron, Roland; Bringhurst, F. Richard; Kronenberg, Henry M.

doi:10.1016/j.cmet.2009.12.007

Cited by 205 publications

(169 citation statements)

References 39 publications

(54 reference statements)

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“…Despite reports that PTH signal transduction downregulates Dkk-1 expression in vitro, treatment with recombinant PTH has been reported to increase serum levels of Dkk-1 in osteoporotic patients (20,31,32). Moreover, Dkk-1 expression has been reported to be positively correlated with bone mineral density in bone biopsy specimens of postmenopausal women and also with bone loss in arthritic patients (33,34).…”

Section: Discussionmentioning

confidence: 96%

Sclerostin and Dickkopf-1 in Renal Osteodystrophy

Cejka¹,

Herberth²,

Branscum³

et al. 2011

Clinical Journal of the American Society of Nephrology

222

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: Discussionmentioning

confidence: 96%

Sclerostin and Dickkopf-1 in Renal Osteodystrophy

Cejka¹,

Herberth²,

Branscum³

et al. 2011

Clinical Journal of the American Society of Nephrology

222

176

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“…DKK1 is a canonical Wnt antagonist and thus DKK1 heterozygous mouse are a genetic model of increased canonical Wnt signaling [58]. When we examined DKK1 heterozygous mice, TLE3 mRNA levels in BMSCs from DKK1 heterozygous mice were elevated in comparison to wild-type littermates (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Expression of TLE3 by bone marrow stromal cells is regulated by canonical Wnt signaling

Kokabu¹,

Sato²,

Ohte³

et al. 2014

FEBS Letters

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Edited by Zhijie ChangKeywords: Osteoblastogenesis Osteoporosis Wnt Groucho Transducing-like enhancer of split Co-repressor a b s t r a c t Transducing-like enhancer of split 3 (TLE3), one of the Groucho/TLE family members, targets Runx2 transcription and suppresses osteoblast differentiation in bone marrow stromal cells (BMSCs). Here, we identify Wnt responsive elements of the TLE3 promoter region through comparative genomic and functional analyses and show that expression of TLE3 is increased by Wnt signaling, which is important for osteoblast differentiation. We also demonstrated that TLE3 is able to suppress canonical Wnt signaling in BMSCs. Taken together, our data suggest that induction of TLE3 by Wnt signaling is part of a negative feedback loop active during osteoblast differentiation.

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“…(20) Mineral apposition rate was determined by intraperitoneal injection of 0.25% calcein (10 mL/g body weight) at 5 and 2 days before sacrifice. Bones were fixed and embedded in methyl methacrylate resin.…”

Section: Analysis Of Bone Histomorphometrymentioning

confidence: 99%

Misexpression of Dickkopf-1 in endothelial cells, but not in chondrocytes or hypertrophic chondrocytes, causes defects in endochondral ossification

Oh¹,

Ryu²,

Jeon³

et al. 2012

Journal of Bone and Mineral Research

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Developing cartilage serves as a template for long-bone development during endochondral ossification. Although the coupling of cartilage and bone development with angiogenesis is an important regulatory step for endochondral ossification, the molecular mechanisms are poorly understood. One possible mechanism involves the action of Dickkopf (DKK), which is a family of soluble canonical Wnt antagonists with four members (DKK1-4). We initially observed opposite expression patterns of Dkk1 and Dkk2 during angiogenesis and chondrocyte differentiation: downregulation of Dkk1 and upregulation of Dkk2. We examined the in vivo role of Dkk1 and Dkk2 in linking cartilage/bone development and angiogenesis by generating transgenic (TG) mice that specifically express Dkk1 or Dkk2 in chondrocytes, hypertrophic chondrocytes, or endothelial cells. Despite specific expression pattern during cartilage development, chondrocyte-and hypertrophic chondrocyte-specific Dkk1 and Dkk2 TG mice showed normal developmental phenotypes. However, Dkk1 misexpression in endothelial cells resulted in defects of endochondral ossification and reduced skeletal size. The defects are caused by the inhibition of angiogenesis in developing bone and subsequent inhibition of apoptosis of hypertrophic chondrocytes and cartilage resorption. ß

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Suppression of Wnt Signaling by Dkk1 Attenuates PTH-Mediated Stromal Cell Response and New Bone Formation

Cited by 205 publications

References 39 publications

Sclerostin and Dickkopf-1 in Renal Osteodystrophy

Sclerostin and Dickkopf-1 in Renal Osteodystrophy

Expression of TLE3 by bone marrow stromal cells is regulated by canonical Wnt signaling

Misexpression of Dickkopf-1 in endothelial cells, but not in chondrocytes or hypertrophic chondrocytes, causes defects in endochondral ossification

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