Contributions of Dickkopf‐1 to Obesity‐Induced Bone Loss and Marrow Adiposity

Colditz, Juliane; Picke, Ann-Kristin; Hofbauer, Lorenz C.; Rauner, Martina

doi:10.1002/jbm4.10364

Cited by 14 publications

(15 citation statements)

References 76 publications

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“…Despite elevated levels of Dkk1 in the serum of T1DM mice, deletion of osteogenic Dkk1 did not affect weight development, fat distribution or glucose tolerance in diabetic mice. This is in line with our previous study in a high-fat diet model, in which lack of osteogenic Dkk1 also did not affect metabolic parameters 30 . Thus, these data suggest that the local production of Dkk1 by mature osteoblasts and osteocytes does not act in an endocrine way to affect glucose metabolism.…”

Section: Discussionsupporting

confidence: 93%

Role of osteogenic Dickkopf-1 in bone remodeling and bone healing in mice with type I diabetes mellitus

Hildebrandt

Colditz

Dutra

et al. 2021

Sci Rep

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Type 1 diabetes mellitus (T1DM) is associated with low bone mass and a higher risk for fractures. Dickkopf-1 (Dkk1), which inhibits Wnt signaling, osteoblast function, and bone formation, has been found to be increased in the serum of patients with T1DM. Here, we investigated the functional role of Dkk1 in T1DM-induced bone loss in mice. T1DM was induced in 10-week-old male mice with Dkk1-deficiency in late osteoblasts/osteocytes (Dkk1f/f;Dmp1-Cre, cKO) and littermate control mice by 5 subsequent injections of streptozotocin (40 mg/kg). Age-matched, non-diabetic control groups received citrate buffer instead. At week 12, calvarial defects were created in subgroups of each cohort. After a total of 16 weeks, weight, fat, the femoral bone phenotype and the area of the bone defect were analyzed using µCT and dynamic histomorphometry. During the experiment, diabetic WT and cKO mice did not gain body weight compared to control mice. Further they lost their perigonadal and subcutaneous fat pads. Diabetic mice had highly elevated serum glucose levels and impaired glucose tolerance, regardless of their Dkk1 levels. T1DM led to a 36% decrease in trabecular bone volume in Cre− negative control animals, whereas Dkk1 cKO mice only lost 16%. Of note, Dkk1 cKO mice were completely protected from T1DM-induced cortical bone loss. T1DM suppressed the bone formation rate, the number of osteoblasts at trabecular bone, serum levels of P1NP and bone defect healing in both, Dkk1-deficient and sufficient, mice. This may be explained by increased serum sclerostin levels in both genotypes and the strict dependence on bone formation for bone defect healing. In contrast, the number of osteoclasts and TRACP 5b serum levels only increased in diabetic control mice, but not in Dkk1 cKO mice. In summary, Dkk1 derived from osteogenic cells does not influence the development of T1DM but plays a crucial role in T1DM-induced bone loss in male mice by regulating osteoclast numbers.

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Section: Discussionsupporting

confidence: 93%

Role of osteogenic Dickkopf-1 in bone remodeling and bone healing in mice with type I diabetes mellitus

Hildebrandt

Colditz

Dutra

et al. 2021

Sci Rep

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“…Besides, AGA is manifested severely in the obese population [ 47 , 48 ]. Concomitantly, DKK1 is hypothesized as a potential biomarker in obesity [ 49 , 50 ]. Additionally, Kim et al have demonstrated that treatment with minoxidil—a common drug for hair-loss—downregulated DKK1 and TGF-β in human keratinocyte cells [ 51 ].…”

Section: Dkk1 Implication In Agamentioning

confidence: 99%

Perspectives on miRNAs Targeting DKK1 for Developing Hair Regeneration Therapy

Papukashvili

Rcheulishvili

Liu

et al. 2021

Cells

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Androgenetic alopecia (AGA) remains an unsolved problem for the well-being of humankind, although multiple important involvements in hair growth have been discovered. Up until now, there is no ideal therapy in clinical practice in terms of efficacy and safety. Ultimately, there is a strong need for developing a feasible remedy for preventing and treating AGA. The Wnt/β-catenin signaling pathway is critical in hair restoration. Thus, AGA treatment via modulating this pathway is rational, although challenging. Dickkopf-related protein 1 (DKK1) is distinctly identified as an inhibitor of canonical Wnt/β-catenin signaling. Thus, in order to stimulate the Wnt/β-catenin signaling pathway, inhibition of DKK1 is greatly demanding. Studying DKK1-targeting microRNAs (miRNAs) involved in the Wnt/β-catenin signaling pathway may lay the groundwork for the promotion of hair growth. Bearing in mind that DKK1 inhibition in the balding scalp of AGA certainly makes sense, this review sheds light on the perspectives of miRNA-mediated hair growth for treating AGA via regulating DKK1 and, eventually, modulating Wnt/β-catenin signaling. Consequently, certain miRNAs regulating the Wnt/β-catenin signaling pathway via DKK1 inhibition might represent attractive candidates for further studies focusing on promoting hair growth and AGA therapy.

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“…Thus, preferential downregulation of S1PR1 indicates reduced osteoimmunological response in FLT3 ITD AML samples. DKK1, which is secreted from mature OBs, implements a negative feedback to Wnt/β-catenin signalling of OB precursor cells and therefore downregulates OB formation [ 41 , 42 ]. Expression of DKK1 was downregulated in FLT3 ITD-positive AML samples, although only in the Metzeler GSE12417-GPL96 data set was this significant.…”

Section: Resultsmentioning

confidence: 99%

Aberrant Bone Homeostasis in AML Is Associated with Activated Oncogenic FLT3-Dependent Cytokine Networks

Bär

Ast

Meyer

et al. 2020

Cells

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Acute myeloid leukaemia (AML) is a haematopoietic malignancy caused by a combination of genetic and epigenetic lesions. Activation of the oncoprotein FLT3 ITD (Fms-like tyrosine kinase with internal tandem duplications) represents a key driver mutation in 25–30% of AML patients. FLT3 is a class III receptor tyrosine kinase, which plays a role in cell survival, proliferation, and differentiation of haematopoietic progenitors of lymphoid and myeloid lineages. Mutant FLT3 ITD results in an altered signalling quality, which causes cell transformation. Recent evidence indicates an effect of FLT3 ITD on bone homeostasis in addition to haematological aberrations. Using gene expression data repositories of FLT3 ITD-positive AML patients, we identified activated cytokine networks that affect the formation of the haematopoietic niche by controlling osteoclastogenesis and osteoblast functions. In addition, aberrant oncogenic FLT3 signalling of osteogenesis-specific cytokines affects survival of AML patients and may be used for prognosis. Thus, these data highlight the intimate crosstalk between leukaemic and osteogenic cells within the osteohaematopoietic niche.

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Contributions of Dickkopf‐1 to Obesity‐Induced Bone Loss and Marrow Adiposity

Cited by 14 publications

References 76 publications

Role of osteogenic Dickkopf-1 in bone remodeling and bone healing in mice with type I diabetes mellitus

Role of osteogenic Dickkopf-1 in bone remodeling and bone healing in mice with type I diabetes mellitus

Perspectives on miRNAs Targeting DKK1 for Developing Hair Regeneration Therapy

Aberrant Bone Homeostasis in AML Is Associated with Activated Oncogenic FLT3-Dependent Cytokine Networks

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