Advanced Molecular Profiling in Vivo Detects Novel Function of Dickkopf-3 in the Regulation of Bone Formation

Aslan, Hadi; Ravid-Amir, Osnat; Clancy, Brian M.; Rezvankhah, Saeid; Pittman, Debra D.; Pelled, Gadi; Turgeman, Gadi; Zilberman, Yoram; Gazit, Zulma; Hoffmann, Andrea; Groß, Gerhard; Domany, Eytan; PhD, Dmd Dan Gazit

doi:10.1359/jbmr.060819

Cited by 32 publications

(39 citation statements)

References 30 publications

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“…In present study, the expression patterns of type IV collagen and Dkk3 were different, and the two molecules were not co-expressed. Dkk3 appeared to be related not to the tissue formation, which requires vascularization, but rather to the differentiation of avascular tissue, including cartilage tissue of the fracture callus, as reported previously [25].…”

Section: Discussionsupporting

confidence: 75%

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Identification of a progenitor cell population destined to form fracture fibrocartilage callus in Dickkopf-related protein 3–green fluorescent protein reporter mice

et al. 2015

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Fracture healing is a complex biological process involving the proliferation of mesenchymal progenitor cells, and chondrogenic, osteogenic, and angiogenic differentiation. The mechanisms underlying the proliferation and differentiation of mesenchymal progenitor cells remain unclear. Here, we demonstrate Dickkopf-related protein 3 (Dkk3) expression in periosteal cells using Dkk3-green fluorescent protein reporter mice. We found that proliferation of mesenchymal progenitor cells began in the periosteum, involving Dkk3-positive cell proliferation near the fracture site. In addition, Dkk3 was expressed in fibrocartilage cells together with smooth muscle α-actin and Col3.6 in the early phase of fracture healing as a cell marker of fibrocartilage cells. Dkk3 was not expressed in mature chondrogenic cells or osteogenic cells. Transient expression of Dkk3 disappeared in the late phase of fracture healing, except in the superficial periosteal area of fracture callus. The Dkk3 expression pattern differed in newly formed type IV collagen positive blood vessels and the related avascular tissue. This is the first report that shows Dkk3 expression in the periosteum at a resting state and in fibrocartilage cells during the fracture healing process, which was associated with smooth muscle α-actin and Col3.6 expression in mesenchymal progenitor cells. These fluorescent mesenchymal lineage cells may be useful for future studies to better understand fracture healing.

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Section: Discussionsupporting

confidence: 75%

“…Other chondrogenic factors may compensate for Dkk3 deficiency in vivo. Another study found that Dkk3 suppressed endochondral ossification [25]. The study authors mentioned that Dkk3 exerted a negative effect on osteogenesis, but also indicated that Dkk3 did not negatively affect chondrogenic proliferation.…”

Section: Discussionmentioning

confidence: 93%

Identification of a progenitor cell population destined to form fracture fibrocartilage callus in Dickkopf-related protein 3–green fluorescent protein reporter mice

et al. 2015

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“…Interestingly, we found reduced bone expression of the Wnt inhibitors Dkk3, Sost, Sfrp2 and Sfrp3 in Sfrp4 -/-mice. These Wnt antagonists suppress osteoblast formation and bone growth (21)(22)(23)(24)(25)(26)(27). However, only mice deficient in Sost and Sfrp3 have increased bone mass (28 -32).…”

Section: Discussionmentioning

confidence: 99%

Loss of SFRP4 Alters Body Size, Food Intake, and Energy Expenditure in Diet-Induced Obese Male Mice

et al. 2015

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Secreted frizzled-related protein 4 (SFRP4) is an extracellular regulator of the wingless-type mouse mammary tumor virus integration site family (WNT) pathway. SFRP4 has been implicated in adipocyte dysfunction, obesity, insulin resistance, and impaired insulin secretion in patients with type 2 diabetes. However, the exact role of SFRP4 in regulating whole-body metabolism and glucose homeostasis is unknown. We show here that male Sfrp4(-/-) mice have increased spine length and gain more weight when fed a high-fat diet. The body composition and body mass per spine length of diet-induced obese Sfrp4(-/-) mice is similar to wild-type littermates, suggesting that the increase in body weight can be accounted for by their longer body size. The diet-induced obese Sfrp4(-/-) mice have reduced energy expenditure, food intake, and bone mineral density. Sfrp4(-/-) mice have normal glucose and insulin tolerance and β-cell mass. Diet-induced obese Sfrp4(-/-) and control mice show similar impairments of glucose tolerance and a 5-fold compensatory expansion of their β-cell mass. In summary, our data suggest that loss of SFRP4 alters body length and bone mineral density as well as energy expenditure and food intake. However, SFRP4 does not control glucose homeostasis and β-cell mass in mice.

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“…It was demonstrated that the DKK3 gene was downregulated in DFCs upon mineral induction, supplying a novel target to control the osteogenic differentiation of DFCs. Notably, a recent microarray study of in vivo -implanted C3H10T1/2 cells expressing BMP2 also implicated DKK3 as a pivotal gene in endochondral bone formation (37). Consequently, the osteogenic differentiation of DFCs by controlling the expression of DKK3 was focused on in subsequent experiments.…”

Section: Discussionmentioning

confidence: 99%

Dickkopf-related protein 3 negatively regulates the osteogenic differentiation of rat dental follicle cells

Zhang

Ling

et al. 2017

Molecular Medicine Reports

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The present study aimed to investigate the effect of Dickkopf-related protein 3 (DKK3) on osteogenic differentiation of rat dental follicle cells (DFCs). A PCR array analysis of Wnt pathway activation in DFCs identified genes dysregulated by mineral induction. Among them, DKK3expression levels were decreased, and further experiments were conducted to investigate its role in DFC osteogenesis. By comparing DFCs grown in normal growth and mineral-induction media for 4 weeks, the present study confirmed that DKK3 was a potential target gene of osteogenesis through reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting (WB). A short hairpin RNA (shRNA) was introduced into DFCs using a lentiviral vector to inhibit DKK3 expression. An alkaline phosphatase (ALP) activity assay and Alizarin Red staining were performed to observe the DKK3-shRNA DFCs. In addition, the osteogenic differentiation of DKK3-shRNA DFCs was analyzed by RT-qPCR and WB. In vivo, DKK3-shRNA DFCs seeded on hydroxyapatite/β-tricalcium phosphate (HA/TCP) scaffolds were transplanted into the subcutaneous tissue of mice with severe combined immunodeficiency, followed by hematoxylin-eosin and Masson staining. The results confirmed that DKK3 expression was downregulated during mineral induction in rat DFCs. Lentivirus-mediated expression of DKK3 shRNA in DFCs promoted calcified-nodule formation, ALP activity and the expression of β-catenin, runt-related transcription factor 2 and osteocalcin, compared with control cells. In vivo, the implanted section presented the majority of newly formed osteoid matrices and collagen, with limited space between the HA/TCP scaffolds and matrices. In conclusion, DKK3 expression negatively regulates the osteogenic differentiation of DFCs and, conversely, downregulation of DKK3 may enhance DFC osteogenesis.

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Advanced Molecular Profiling in Vivo Detects Novel Function of Dickkopf-3 in the Regulation of Bone Formation

Cited by 32 publications

References 30 publications

Identification of a progenitor cell population destined to form fracture fibrocartilage callus in Dickkopf-related protein 3–green fluorescent protein reporter mice

Identification of a progenitor cell population destined to form fracture fibrocartilage callus in Dickkopf-related protein 3–green fluorescent protein reporter mice

Loss of SFRP4 Alters Body Size, Food Intake, and Energy Expenditure in Diet-Induced Obese Male Mice

Dickkopf-related protein 3 negatively regulates the osteogenic differentiation of rat dental follicle cells

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