Publications by authors named "Martina Rauner"

140 Publications

Hypoxia-Inducible Factors Regulate Osteoclasts in Health and Disease.

Front Cell Dev Biol 2021 18;9:658893. Epub 2021 Mar 18.

Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nurnberg (FAU) and Universitatsklinikum Erlangen, Erlangen, Germany.

Hypoxia-inducible factors (HIFs) have become key transcriptional regulators of metabolism, angiogenesis, erythropoiesis, proliferation, inflammation and metastases. HIFs are tightly regulated by the tissue microenvironment. Under the influence of the hypoxic milieu, HIF proteins allow the tissue to adapt its response. This is especially critical for bone, as it constitutes a highly hypoxic environment. As such, bone structure and turnover are strongly influenced by the modulation of oxygen availability and HIFs. Both, bone forming osteoblasts and bone resorbing osteoclasts are targeted by HIFs and modulators of oxygen tension. Experimental and clinical data have delineated the importance of HIF responses in different osteoclast-mediated pathologies. This review will focus on the influence of HIF expression on the regulation of osteoclasts in homeostasis as well as during inflammatory and malignant bone diseases.
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http://dx.doi.org/10.3389/fcell.2021.658893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014084PMC
March 2021

Mice lacking DKK1 in T cells exhibit high bone mass and are protected from estrogen-deficiency-induced bone loss.

iScience 2021 Mar 23;24(3):102224. Epub 2021 Feb 23.

Department of Medicine III, Division of Endocrinology, Diabetes and Bone Diseases, Technische Universität Dresden, Dresden 01307, Germany.

The Wnt inhibitor Dickkopf-1 (DKK1) is a negative regulator of bone formation and bone mass and is dysregulated in various bone diseases. How DKK1 contributes to postmenopausal osteoporosis, however, remains poorly understood. Here, we show that mice lacking DKK1 in T cells are protected from ovariectomy-induced bone loss. Ovariectomy activated CD4+ and CD8+ T cells and increased their production of DKK1. Co-culture of activated T cells with osteoblasts inhibited Wnt signaling in osteoblasts, leading to impaired differentiation. Importantly, DKK1 expression in T cells also controlled physiological bone remodeling. T-cell-deficient knock-out mice had a higher bone mass with an increased bone formation rate and decreased numbers of osteoclasts compared with controls, a phenotype that was rescued by adoptive transfer of wild-type T cells. Thus, these findings highlight that T cells control bone remodeling in health and disease via their expression of DKK1.
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http://dx.doi.org/10.1016/j.isci.2021.102224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961106PMC
March 2021

Metastatic Spread in Prostate Cancer Patients Influencing Radiotherapy Response.

Front Oncol 2020 4;10:627379. Epub 2021 Mar 4.

National Center for Tumor Diseases (NCT), Dresden, Germany.

Radiotherapy and surgery are curative treatment options for localized prostate cancer (PCa) with a 5-year survival rate of nearly 100%. Once PCa cells spread into distant organs, such as bone, the overall survival rate of patients drops dramatically. The metastatic cascade and organotropism of PCa cells are regulated by different cellular subtypes, organ microenvironment, and their interactions. This cross-talk leads to pre-metastatic niche formation that releases chemo-attractive factors enforcing the formation of distant metastasis. Biological characteristics of PCa metastasis impacting on metastatic sites, burden, and latency is of clinical relevance. Therefore, the implementation of modern hybrid imaging technologies into clinical routine increased the sensitivity to detect metastases at earlier stages. This enlarged the number of PCa patients diagnosed with a limited number of metastases, summarized as oligometastatic disease. These patients can be treated with androgen deprivation in combination with local-ablative radiotherapy or radiopharmaceuticals directed to metastatic sites. Unfortunately, the number of patients with disease recurrence is high due to the enormous heterogeneity within the oligometastatic patient population and the lack of available biomarkers with predictive potential for metastasis-directed radiotherapy. Another, so far unmet clinical need is the diagnosis of minimal residual disease before onset of clinical manifestation and/or early relapse after initial therapy. Here, monitoring of circulating and disseminating tumor cells in PCa patients during the course of radiotherapy may give us novel insight into how metastatic spread is influenced by radiotherapy and vice versa. In summary, this review critically compares current clinical concepts for metastatic PCa patients and discuss the implementation of recent preclinical findings improving our understanding of metastatic dissemination and radiotherapy resistance into standard of care.
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http://dx.doi.org/10.3389/fonc.2020.627379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971112PMC
March 2021

Osteoporosis Treatment with Anti-Sclerostin Antibodies-Mechanisms of Action and Clinical Application.

J Clin Med 2021 Feb 16;10(4). Epub 2021 Feb 16.

Division of Endocrinology, Center for Bone Quality, Department of Medicine, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.

Osteoporosis is characterized by reduced bone mass and disruption of bone architecture, resulting in increased risk of fragility fractures and significant long-term disability. Although both anti-resorptive treatments and osteoanabolic drugs, such as parathyroid hormone analogues, are effective in fracture prevention, limitations exist due to lack of compliance or contraindications to these drugs. Thus, there is a need for novel potent therapies, especially for patients at high fracture risk. Romosozumab is a monoclonal antibody against sclerostin with a dual mode of action. It enhances bone formation and simultaneously suppresses bone resorption, resulting in a large anabolic window. In this opinion-based narrative review, we highlight the role of sclerostin as a critical regulator of bone mass and present human diseases of sclerostin deficiency as well as preclinical models of genetically modified sclerostin expression, which led to the development of anti-sclerostin antibodies. We review clinical studies of romosozumab in terms of bone mass accrual and anti-fracture activity in the setting of postmenopausal and male osteoporosis, present sequential treatment regimens, and discuss its safety profile and possible limitations in its use. Moreover, an outlook comprising future translational applications of anti-sclerostin antibodies in diseases other than osteoporosis is given, highlighting the clinical significance and future scopes of Wnt signaling in these settings.
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http://dx.doi.org/10.3390/jcm10040787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920044PMC
February 2021

High stroma-derived WNT5A is an indicator for low-risk prostate cancer.

FEBS Open Bio 2021 Apr 11;11(4):1186-1194. Epub 2021 Mar 11.

Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III and University Center for Healthy Aging, Technische Universität Dresden, Germany.

Prostate cancer (PCa) is a major cause of cancer-related death in men. Tumor-derived protein derived from Wnt5A gene (WNT5A) plays an important role in primary and metastatic PCa. Surrounding stroma cells also produce WNT5A, which may modulate the biology of PCa. Here, we assessed the role of stroma-derived WNT5A (stWNT5A) in primary PCa. A tissue microarray of samples obtained from 400 patients who underwent radical prostatectomy and control samples from 41 patients with benign prostate hyperplasia (BPH) was immunohistochemically assessed for expression of stWNT5A. The cores were scored for staining intensity: 0 (no staining), 1 (weak), 2 (moderate), or 3 (strong) and the stained stromal surface area: 0 (0%), 1 (1-25%), 2 (26-50%), 3 (51-75%), or 4 (76-100%). Gleason Score (GS) and TNM-stage were assessed by stratifying the cohort into high-risk (≥ pT3, pN1, GS ≥ 8) and non-high-risk patients. Ki67 and TUNEL assays were performed to assess proliferation and apoptosis. Expression of stWNT5A in BPH and tumor-free control samples was 1.2-fold higher compared to tumor samples (P < 0.001). Non-high-risk patients had a higher stWNT5A score than high-risk patients (P < 0.05). stWNT5A expression was not correlated with overall and cancer-specific survival. Proliferation (r  = 0.038, P < 0.001) and apoptosis (r  = 0.277, P < 0.001) negatively correlated with stWNT5A expression. In summary, we show that expression of stWNT5A is higher in benign tissue and non-high-risk PCa. Stroma-derived Wnt signaling and tumor-derived Wnt may differentially impact on tumor behavior. Future studies are warranted to dissect the Wnt profile in tumor vs. surrounding stroma tissues.
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http://dx.doi.org/10.1002/2211-5463.13131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016115PMC
April 2021

Late-onset hypogonadism: Clinical evidence, biological aspects and evolutionary considerations.

Ageing Res Rev 2021 May 18;67:101301. Epub 2021 Feb 18.

Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany.

The growing life expectancy in modern societies has raised scientific interest in identifying medical interventions to alleviate age-associated pathologies such as vascular calcification, cognitive decline, sarcopenia, osteoporosis and sexual dysfunction. Although no such single treatment has thus far been established in humans, some clinicians and patients have set their hopes on testosterone replacement therapy (TRT) as a potential "fountain of youth" for aging men. While TRT has proven effective in ameliorating distinct symptoms of late-onset hypogonadism (LOH), its safety remains to be demonstrated. Besides humans, multiple other species exhibit age-related reductions in circulating testosterone levels, raising the question whether such changes are an inherent, pathological feature of growing organismal age or rather reflect an adaptive response. In this manuscript, we apply key principles of evolutionary medicine to testosterone biology and LOH to provide a novel perspective on these two fields. Additionally, we discuss insightful data derived from the animal kingdom to illustrate the plasticity of individual testosterone trajectories across the lifespan, outline cost-benefit-considerations of TRT in LOH and highlight potential caveats of such therapies.
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http://dx.doi.org/10.1016/j.arr.2021.101301DOI Listing
May 2021

Toward Biofabrication of Resorbable Implants Consisting of a Calcium Phosphate Cement and Fibrin-A Characterization In Vitro and In Vivo.

Int J Mol Sci 2021 Jan 26;22(3). Epub 2021 Jan 26.

Department of Oral and Maxillofacial Surgery Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Augustenburger Platz 1, 13353 Berlin, Germany.

Cleft alveolar bone defects can be treated potentially with tissue engineered bone grafts. Herein, we developed novel biphasic bone constructs consisting of two clinically certified materials, a calcium phosphate cement (CPC) and a fibrin gel that were biofabricated using 3D plotting. The fibrin gel was loaded with mesenchymal stromal cells (MSC) derived from bone marrow. Firstly, the degradation of fibrin as well as the behavior of cells in the biphasic system were evaluated in vitro. Fibrin degraded quickly in presence of MSC. Our results showed that the plotted CPC structure acted slightly stabilizing for the fibrin gel. However, with passing time and fibrin degradation, MSC migrated to the CPC surface. Thus, the fibrin gel could be identified as cell delivery system. A pilot study in vivo was conducted in artificial craniofacial defects in Lewis rats. Ongoing bone formation could be evidenced over 12 weeks but the biphasic constructs were not completely osseous integrated. Nevertheless, our results show that the combination of 3D plotted CPC constructs and fibrin as suitable cell delivery system enables the fabrication of novel regenerative implants for the treatment of alveolar bone defects.
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http://dx.doi.org/10.3390/ijms22031218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865817PMC
January 2021

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

Sci Rep 2021 Jan 21;11(1):1920. Epub 2021 Jan 21.

Department of Medicine III and Center for Healthy Aging, Medical Faculty, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany.

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 (Dkk1;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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http://dx.doi.org/10.1038/s41598-021-81543-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820472PMC
January 2021

Emerging Players in Prostate Cancer-Bone Niche Communication.

Trends Cancer 2021 02 24;7(2):112-121. Epub 2020 Oct 24.

Department of Medicine III and Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany. Electronic address:

Patients with advanced prostate cancer (PCa) frequently develop skeletal metastases that are associated with fractures, disability, and increased mortality. Within the bone metastatic niche, mutual interactions between tumor cells and osteoblasts have been proposed as major contributors of osteotropism by PCa. Here, we highlight the emerging role of PCa-derived extracellular vesicles (EVs) in reprogramming osteoblasts and support of premetastatic niche formation. We also develop the concept of cancer-associated osteoblasts (CAOs) and outline the potential of PCa cells to acquire an osteoblastic phenotype, termed osteomimicry, as two strategies that PCa utilizes to create a favorable protected niche. Finally, we delineate future research that may help to deconstruct the complexity of PCa osteotropism.
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http://dx.doi.org/10.1016/j.trecan.2020.09.006DOI Listing
February 2021

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

Cells 2020 11 9;9(11). Epub 2020 Nov 9.

Institute of Molecular Cell Biology, Center for Molecular Biomedicine (CMB), Jena University Hospital, 07745 Jena, Germany.

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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http://dx.doi.org/10.3390/cells9112443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697865PMC
November 2020

The Bone Morphogenetic Protein Pathway: The Osteoclastic Perspective.

Front Cell Dev Biol 2020 16;8:586031. Epub 2020 Oct 16.

Department of Medicine III, Technische Universität Dresden, Dresden, Germany.

Bone health crucially relies on constant bone remodeling and bone regeneration, both tightly controlled processes requiring bone formation and bone resorption. Plenty of evidence identifies bone morphogenetic proteins (BMP) as major players in osteoblast differentiation and thus, bone formation. However, in recent past years, researchers also increasingly reported on the pivotal role of these multi-functional growth factors in osteoclast formation and activity. This review aims to summarize the current knowledge of BMP signaling within the osteoclast lineage, its role in bone resorption, and osteoblast-osteoclast coupling. Furthermore, subsequent clinical implications for recombinant BMP therapy will be discussed in view of recent preclinical and clinical studies.
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http://dx.doi.org/10.3389/fcell.2020.586031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7597383PMC
October 2020

Hypoxia Pathway Proteins are Master Regulators of Erythropoiesis.

Int J Mol Sci 2020 Oct 30;21(21). Epub 2020 Oct 30.

Institute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, 01307 Dresden, Germany.

Erythropoiesis is a complex process driving the production of red blood cells. During homeostasis, adult erythropoiesis takes place in the bone marrow and is tightly controlled by erythropoietin (EPO), a central hormone mainly produced in renal EPO-producing cells. The expression of EPO is strictly regulated by local changes in oxygen partial pressure (pO) as under-deprived oxygen (hypoxia); the transcription factor hypoxia-inducible factor-2 induces EPO. However, erythropoiesis regulation extends beyond the well-established hypoxia-inducible factor (HIF)-EPO axis and involves processes modulated by other hypoxia pathway proteins (HPPs), including proteins involved in iron metabolism. The importance of a number of these factors is evident as their altered expression has been associated with various anemia-related disorders, including chronic kidney disease. Eventually, our emerging understanding of HPPs and their regulatory feedback will be instrumental in developing specific therapies for anemic patients and beyond.
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http://dx.doi.org/10.3390/ijms21218131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662373PMC
October 2020

Interactions of Anemia, FGF-23, and Bone in Healthy Adults-Results From the Study of Health in Pomerania (SHIP).

J Clin Endocrinol Metab 2021 Jan;106(1):e288-e299

Department of Medicine III and Center for Healthy Aging, Dresden Technical University Medical Center, Dresden, Germany.

Context: Osteoporosis and anemia are among the most common diseases in the aging population with an increasing prevalence worldwide.

Objective: As the bone-derived hormone fibroblast growth factor 23 (FGF-23) was recently reported to regulate erythropoiesis, we examined age-related associations between hemoglobin levels and bone quality, bone turnover, and FGF-23 concentrations.

Design: We used data from more than 5000 adult subjects who participated in the population-based cohorts of the Study of Health in Pomerania (SHIP and SHIP-Trend). Bone quality was assessed by quantitative ultrasound at the heel, bone turnover by measurement of carboxy-terminal telopeptide of type I collagen (CTX), and intact amino-terminal propeptide of type I procollagen (P1NP) serum concentrations, respectively. Anemia was defined as hemoglobin <13 g/dL in men and <12 g/dL in women. Carboxy-terminal FGF-23 levels were measured in plasma in a subset of 852 subjects.

Results: Anemic subjects had poorer bone quality, higher fracture risk, and lower serum levels of P1NP than nonanemic individuals. Linear regression models revealed positive associations between hemoglobin and bone quality in subjects aged 40 or above and inverse associations with CTX in subjects aged 60 or above. Hemoglobin and FGF-23 concentrations were inversely associated, while FGF-23 was not related to bone quality or turnover.

Conclusion: Our data corroborate a close link between FGF-23 and anemia, which is related to poor bone quality in elderly people. We observed no direct association of FGF-23 with bone parameters. Further studies are needed clarifying the role of FGF-23 on bone and red blood cell production.
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http://dx.doi.org/10.1210/clinem/dgaa716DOI Listing
January 2021

Nanocytometer for smart analysis of peripheral blood and acute myeloid leukemia: a pilot study.

Nano Lett 2020 09 27;20(9):6572-6581. Epub 2020 Aug 27.

Max Bergmann Center of Biomaterials and Institute for Materials Science, Dresden University of Technology, Budapesterstrasse 27, 01069 Dresden, Germany.

We realize an ultracompact nanocytometer for real-time impedimetric detection and classification of subpopulations of living cells. Nanoscopic nanowires in a microfluidic channel act as nanocapacitors and measure in real time the change of the amplitude and phase of the output voltage and, thus, the electrical properties of living cells. We perform the cell classification in the human peripheral blood (PBMC) and demonstrate for the first time the possibility to discriminate monocytes and of lymphocytes in a label-free format. Further, we demonstrate that the PBMC of acute myeloid leukemia and healthy samples grant the label free identification of the disease. Using the algorithm based on machine learning, we generated to discriminate healthy donors and leukemia patients. Such a solution has the potential to improve the traditional diagnostics approaches with respect to the overall cost and time effort, in a label-free format, and restrictions of the complex data analysis.
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http://dx.doi.org/10.1021/acs.nanolett.0c02300DOI Listing
September 2020

Effects of androgen excess and glucocorticoid exposure on bone health in adult patients with 21-hydroxylase deficiency.

J Steroid Biochem Mol Biol 2020 11 9;204:105734. Epub 2020 Aug 9.

Medizinische Klinik and Poliklinik IV, Klinikum der Universität München, LMU München, Munich, Germany. Electronic address:

Context: This study aimed to determine the role of modifiable predictors on bone health in congenital adrenal hyperplasia (CAH).

Design: Cross-sectional, single center study, including 97 patients (N = 42 men) with classic CAH due to 21-hydroxylase deficiency (N = 65 salt wasting, N = 32 simple virilizing).

Main Outcome Measures: Treatment-related predictors of bone health.

Results: Average T scores (-0.9 ± 1.4 vs. -0.4 ± 1.4; p = 0.036) as well as Z scores (-1.0 ± 1.3 vs. -0.1 ± 1.4; p = 0.012) at the spine in patients with CAH were significantly lower in men than women. While osteoporosis was rare in women, it was documented in 9.1% of men with CAH. There was a significant positive correlation of Z scores at the spine with advancing age in women with CAH (R² = 0.178; p = 0.003). In multivariate analysis, the intake of conventional hydrocortisone (HC) instead of synthetic glucocorticoids was independently associated with a higher bone mineral density (BMD) at the hip region in both sexes. In women, there was a positive association with vitamin D concentrations. Interestingly, higher sodium levels were associated with a lower BMD independent of renin levels and fludrocortisone dosage. Neither in men nor in women, markers of androgen control were predictive for BMD at any site. Markers of bone turnover indicated low bone turnover. No pathological fractures were documented.

Conclusions: Men with CAH are particularly prone to low bone density, while women seem to be relatively protected by androgen excess compared to the general female population. The use of HC instead of synthetic GCs for hormone replacement may translate into better bone health.
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http://dx.doi.org/10.1016/j.jsbmb.2020.105734DOI Listing
November 2020

Increased FGF-23 levels are linked to ineffective erythropoiesis and impaired bone mineralization in myelodysplastic syndromes.

JCI Insight 2020 08 6;5(15). Epub 2020 Aug 6.

Bone Lab Dresden, Department of Medicine III & Center for Healthy Aging, and.

Myelodysplastic syndromes (MDS) are clonal malignant hematopoietic disorders in the elderly characterized by ineffective hematopoiesis. This is accompanied by an altered bone microenvironment, which contributes to MDS progression and higher bone fragility. The underlying mechanisms remain largely unexplored. Here, we show that myelodysplastic NUP98‑HOXD13 (NHD13) transgenic mice display an abnormally high number of osteoblasts, yet a higher fraction of nonmineralized bone, indicating delayed bone mineralization. This was accompanied by high fibroblast growth factor-23 (FGF-23) serum levels, a phosphaturic hormone that inhibits bone mineralization and erythropoiesis. While Fgf23 mRNA expression was low in bone, brain, and kidney of NHD13 mice, its expression was increased in erythroid precursors. Coculturing these precursors with WT osteoblasts induced osteoblast marker gene expression, which was inhibited by blocking FGF-23. Finally, antibody-based neutralization of FGF-23 in myelodysplastic NHD13 mice improved bone mineralization and bone microarchitecture, and it ameliorated anemia. Importantly, higher serum levels of FGF‑23 and an elevated amount of nonmineralized bone in patients with MDS validated the findings. C‑terminal FGF‑23 correlated negatively with hemoglobin levels and positively with the amount of nonmineralized bone. Thus, our study identifies FGF-23 as a link between altered bone structure and ineffective erythropoiesis in MDS with the prospects of a targeted therapeutic intervention.
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http://dx.doi.org/10.1172/jci.insight.137062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455070PMC
August 2020

Erythropoietin receptor in B cells plays a role in bone remodeling in mice.

Theranostics 2020 9;10(19):8744-8756. Epub 2020 Jul 9.

Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Israel.

Erythropoietin (EPO) is a key regulator of erythropoiesis. However, EPO receptors (EPO-Rs) are also expressed on non-erythroid cell types, including myeloid and bone cells. Immune cells also participate in bone homeostasis. B cells produce receptor activator of nuclear factor kappa-Β ligand (RANKL) and osteoprotegerin (OPG), two pivotal regulators of bone metabolism. Here we explored the ability of B cells to transdifferentiate into functional osteoclasts and examined the role of EPO in this process in a murine model. We have combined specifically-designed experimental mouse models and based osteoclastogenesis assays, as well as PCR analysis of gene expression. (i) EPO treatment increased RANKL expression in bone marrow (BM) B cells, suggesting a paracrine effect on osteoclastogenesis; (ii) B cell-derived osteoclastogenesis occured and as demonstrated by B cell lineage tracing in murine models; (iii) B-cell-derived osteoclastogenesis was restricted to Pro-B cells expressing CD115/CSF1-R and is enhanced by EPO; (iv) EPO treatment increased the number of B-cell-derived preosteoclasts (β3CD115), suggesting a physiological rationale for B cell derived osteoclastogenesis; (v) finally, mice with conditional EPO-R knockdown in the B cell lineage (cKD) displayed a higher cortical and trabecular bone mass. Moreover, cKD displayed attenuated EPO-driven trabecular bone loss, an effect that was observed despite the fact that cKD mice attained higher hemoglobin levels following EPO treatment. Our work highlights B cells as an important extra-erythropoietic target of EPO-EPO-R signaling and suggests their involvement in the regulation of bone homeostasis and possibly in EPO-stimulated erythropoietic response. Importantly, we present here for the first time, histological evidence for B cell-derived osteoclastogenesis .
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http://dx.doi.org/10.7150/thno.45845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392011PMC
July 2020

Bioinspired Scaffold Action Under the Extreme Physiological Conditions of Simulated Space Flights: Osteogenesis Enhancing Under Microgravity.

Front Bioeng Biotechnol 2020 8;8:722. Epub 2020 Jul 8.

Department of Chemistry and Pharmacy, University of Sassari, Sassari, Italy.

Prolonged exposure to microgravity (MG) during long-duration space flights is known to induce severe dysregulation of osteoblast functions connected to a significant bone loss, similar to the condition induced by osteoporosis. Hence, we here present MG as a promising model to challenge the effectiveness of new scaffolds designed for bone regeneration in counteracting bone loss. To this end, we carried out an integrative study aimed to evaluate, in the extreme condition of Random Positioning Machine-simulated MG, the osteoinductive potential of nanocrystalline magnesium-doped hydroxyapatite/type I collagen composite scaffold (MHA/Coll), that we previously demonstrated to be an excellent tool for bone tissue engineering. Initially, to test the osteoinductive properties of our bioinspired-scaffold, MHA/Coll structure was fully characterized under MG condition and compared to its static counterpart. Human bone marrow-derived mesenchymal stem cells were used to investigate the scaffold biocompatibility and ability to promote osteogenic differentiation after long-duration exposure to MG (up to 21 days). The results demonstrate that the nanostructure of MHA/Coll scaffold can alleviate MG-induced osteoblast dysfunction, promoting cell differentiation along the osteogenic lineage, with a consequent reduction in the expression of the surface markers CD29, CD44, and CD90. Moreover, these findings were corroborated by the ability of MHA/Coll to induce the expression of genes linked to osteogenesis, including alkaline phosphatase and osteocalcin. This study confirmed MHA/Coll capabilities in promoting osteogenesis even in extreme long-term condition of MG, suggesting MG as an effective challenging model to apply in future studies to validate the ability of advanced scaffolds to counteract bone loss, facilitating their application in translational Regenerative Medicine and Tissue Engineering.
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http://dx.doi.org/10.3389/fbioe.2020.00722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362936PMC
July 2020

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

JBMR Plus 2020 Jun 28;4(6):e10364. Epub 2020 Apr 28.

Department of Medicine III, Center for Healthy Aging Technische Universität Dresden Dresden Germany.

Low bone strength in overweight individuals is a significant medical problem. One important determinant of mesenchymal stem cell fate into osteoblasts or adipocytes is the Wnt signaling pathway. We recently showed that Dickkopf-1 (DKK1), a potent Wnt inhibitor, is upregulated in obese mice. In this study, we investigated the role of DKK1 in the pathogenesis of obesity-induced bone loss using global and tissue-specific KO mice. Obesity was induced in 8-week-old male mice with an inducible global (Rosa26-CreERT2) or osteoprogenitor- (Osx-Cre-) specific deletion of with a high-fat diet (HFD) containing 60% fat. After 12 weeks, body weight, bone volume, bone fat mass, and bone turnover were assessed. mice experienced a similar increase in body weight and white fat pads as control mice. A HFD significantly reduced trabecular bone mass and the bone formation rate in Cre- mice and mice. Interestingly, mice were protected from HFD-induced cortical bone loss. Furthermore, a HFD was associated with increased bone marrow fat in the femur, which was less pronounced in mice. Mice with an osteoprogenitor-specific deletion showed similar results as the global knockout, showing a protection against HFD-induced cortical bone loss and an accumulation of bone marrow fat, but a similar decrease in trabecular bone volume. In summary, DKK1 appears to contribute distinctly to cortical, but not trabecular bone loss in obesity. © 2020 The Authors. published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbm4.10364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285751PMC
June 2020

Serum Profile of microRNAs Linked to Bone Metabolism During Sequential Treatment for Postmenopausal Osteoporosis.

J Clin Endocrinol Metab 2020 08;105(8)

Department of Medicine III, Technische Universität Dresden Medical Centre, Dresden, Germany.

Context: Serum expression of microRNAs (miRs) related to bone metabolism is affected by antiosteoporotic treatment.

Objective: To investigate the effect of sequential treatments on miR expression in postmenopausal women with osteoporosis.

Design: Observational, open label, nonrandomized clinical trial.

Setting: A single-center outpatient clinic.

Patients And Interventions: Denosumab (Dmab) was administered for 12 months in 37 women who were treatment-naïve (naïve group) (n = 11) or previously treated with teriparatide (TPTD group) (n = 20) or zoledronate (ZOL group) (n = 6).

Main Outcome Measures: Relative serum expression of miRs linked to bone metabolism at 3 and 6 months of Dmab treatment.

Results: Baseline relative expression of miR-21a-5p, miR-23a-3p, miR-29a-3p, and miR-338-3p was higher in the TPTD group, while the relative expression of miR-21a-5p was lower in the ZOL group compared to the naïve group. Dmab decreased the relative expression of miR-21a-5p at 3 months (fold change [FC] 0.43, P < 0.001) and 6 months (FC 0.34, P < 0.001), and miR-338-3p and miR-2861 at 6 months (FC 0.31, P = 0.041; FC 0.52, P = 0.016, respectively) in the whole cohort. In subgroup analyses, Dmab decreased the relative expression of miR-21a-5p, miR-29a-3p, miR-338-3p, and miR-2861 at 3 months (FC 0.13, P < 0.001; FC 0.68, P = 0.044; FC 0.46, P = 0.012; and FC 0.16, P < 0.001, respectively) and 6 months (FC 0.1, P < 0.001; FC 0.52, P < 0.001; FC 0.04, P = 0.006; and FC 0.2, P < 0.001, respectively) only within the TPTD group.

Conclusions: TPTD treatment potentially affects the expression of the pro-osteoclastogenic miR-21a-5p and miRs related to the expression of osteoblastic genes RUNX2 (miR23a-3p), COL1 (miR-29a-3p), and HDAC5 (miR-2861), while sequential treatment with Dmab acts in the opposite direction.
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http://dx.doi.org/10.1210/clinem/dgaa368DOI Listing
August 2020

Author Correction: Glucocorticoids suppress Wnt16 expression in osteoblasts in vitro and in vivo.

Sci Rep 2020 Jun 4;10(1):9344. Epub 2020 Jun 4.

Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-65962-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271193PMC
June 2020

Erythropoietin Mediated Bone Loss in Mice Is Dose-Dependent and Mostly Irreversible.

Int J Mol Sci 2020 May 27;21(11). Epub 2020 May 27.

Department of Medicine A, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6423906, Israel.

Recent studies have demonstrated that erythropoietin (EPO) treatment in mice results in trabecular bone loss. Here, we investigated the dose-response relationship between EPO, hemoglobin (Hgb) and bone loss and examined the reversibility of EPO-induced damage. Increasing doses of EPO over two weeks led to a dose-dependent increase in Hgb in young female mice, accompanied by a disproportionate decrease in trabecular bone mass measured by micro-CT (µCT). Namely, increasing EPO from 24 to 540 IU/week produced a modest 12% rise in Hgb (20.2 ± 1.3 mg/dL vs 22.7 ± 1.3 mg/dL), while trabecular bone volume fraction (BV/TV) in the distal femur decreased dramatically (27 ± 8.5% vs 53 ± 10.2% bone loss). To explore the long-term skeletal effects of EPO, we treated mice for two weeks (540 IU/week) and monitored bone mass changes after treatment cessation. Six weeks post-treatment, there was only a partial recovery of the trabecular microarchitecture in the femur and vertebra. EPO-induced bone loss is therefore dose-dependent and mostly irreversible at doses that offer only a minor advantage in the treatment of anemia. Because patients requiring EPO therapy are often prone to osteoporosis, our data advocate for using the lowest effective EPO dose for the shortest period of time to decrease thromboembolic complications and minimize the adverse skeletal outcome.
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http://dx.doi.org/10.3390/ijms21113817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312352PMC
May 2020

Disruption of BMP Signaling Prevents Hyperthyroidism-Induced Bone Loss in Male Mice.

J Bone Miner Res 2020 10 15;35(10):2058-2069. Epub 2020 Jun 15.

Department of Medicine III, Universitätsklinikum Dresden, Technische Universität Dresden, Dresden, Germany.

Thyroid hormones (TH) are key regulators of bone health, and TH excess in mice causes high bone turnover-mediated bone loss. However, the underlying molecular mechanisms of TH actions on bone remain poorly defined. Here, we tested the hypothesis whether TH mediate their effects via the pro-osteogenic bone morphogenetic protein (BMP) signaling pathway in vitro and in vivo. Primary murine osteoblasts treated with 3,3',5-triiodo-L-thyronine (T ) showed an enhanced differentiation potential, which was associated with activated canonical BMP/SMAD signaling reflected by SMAD1/5/8 phosphorylation. Blocking BMP signaling at the receptor (LDN193189) and ligand level (noggin, anti-BMP2/BMP4 neutralizing antibodies) inhibited T -induced osteogenic differentiation. In vivo, TH excess over 4 weeks in male C57BL/6JRj mice led to severe trabecular bone loss with a high bone turnover that was completely prevented by treatment with the BMP ligand scavenger ALK3-Fc. Thus, TH activate the canonical BMP pathway in osteoblasts to promote their differentiation and function. Importantly, this study indicates that blocking the BMP pathway may be an effective strategy to treat hyperthyroidism-induced bone loss. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.4092DOI Listing
October 2020

Disruption of the hepcidin/ferroportin regulatory circuitry causes low axial bone mass in mice.

Bone 2020 08 4;137:115400. Epub 2020 May 4.

Department of Medicine III, Technische Universität Dresden, Dresden, Germany; Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany. Electronic address:

Ferroportin (FPN) is the only known iron exporter. Mutations conferring resistance of FPN to hepcidin-mediated degradation cause the iron overload disorder hereditary hemochromatosis type 4. While iron overload is associated with low bone mass, the mechanisms involved are not completely understood. Here, we aimed to investigate whether the disruption in the hepcidin/FPN axis in Fpn mice and subsequent systemic iron accumulation impacts on bone tissue to a similar extent as in Hfe mice, which are hallmarked by a milder iron overload phenotype. Hfe and Fpn mice show increased plasma iron levels and liver iron content, whereas iron overload was more pronounced in Fpn compared to Hfe mice. Bone volume fraction and trabecular thickness at the femur were not different between 10 and 14-week-old male wild-type (WT), Hfe and Fpn mice. By contrast, both Hfe and Fpn mice exhibited a lower bone volume fraction [Hfe, 24%; Fpn, 33%; p < 0.05] and trabecular thickness [Hfe, 10%; Fpn, 15%; p < 0.05] in the fourth lumbar vertebra compared to WT mice. Analysis of the bone formation rate at the tibia showed no difference in both genotypes, but it was reduced in the vertebral bone of Fpn [36%, p < 0.05] compared to WT mice. Serum levels of the bone formation marker, P1NP, were significantly reduced in both, Hfe and Fpn compared with WT mice [Hfe, 35%; Fpn, 40%; p < 0.05]. Also, the intrinsic differentiation capacity of Fpn osteoblasts was impaired. Osteoclast parameters were not grossly affected. Interestingly, the liver iron content and plasma iron levels negatively correlated with the bone formation rate and serum levels of P1NP. Thus, disruption of the hepcidin/ferroportin regulatory axis in Fpn mice results in axial bone loss due to suppressed bone formation.
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http://dx.doi.org/10.1016/j.bone.2020.115400DOI Listing
August 2020

3D Printing of Bone Grafts for Cleft Alveolar Osteoplasty - Evaluation in a Preclinical Model.

Front Bioeng Biotechnol 2020 25;8:217. Epub 2020 Mar 25.

Centre for Translational Bone, Joint and Soft Tissue Research, University Hospital "Carl Gustav Carus", Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.

One of the most common hereditary craniofacial anomalies in humans are cleft lip and cleft alveolar bone with or without cleft palate. Current clinical practice, the augmentation of the persisting alveolar bone defect by using autologous bone grafts, has considerable disadvantages motivating to an intensive search for alternatives. We developed a novel therapy concept based on 3D printing of biodegradable calcium phosphate-based materials and integration of osteogenic cells allowing fabrication of patient-specific, tissue-engineered bone grafts. Objective of the present study was the evaluation of implants in a rat alveolar cleft model. Scaffolds were designed according to the defect's geometry with two different pore designs (60° and 30° rotated layer orientation) and produced by extrusion-based 3D plotting of a pasty calcium phosphate cement. The scaffolds filled into the artificial bone defect in the palate of adult Lewis rats, showing a good support. Half of the scaffolds were colonized with rat mesenchymal stromal cells (rMSC) prior to implantation. After 6 and 12 weeks, remaining defect width and bone formation were quantified histologically and by microCT. The results revealed excellent osteoconductive properties of the scaffolds, a significant influence of the pore geometry (60° > 30°), but no enhanced defect healing by pre-colonization with rMSC.
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http://dx.doi.org/10.3389/fbioe.2020.00217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109264PMC
March 2020

CD5L Constitutes a Novel Biomarker for Integrated Hepatic Thyroid Hormone Action.

Thyroid 2020 06 21;30(6):908-923. Epub 2020 Apr 21.

Department of Molecular Endocrinology, Center of Brain, Behavior and Metabolism, Institute for Endocrinology and Diabetes, University of Lübeck, Lübeck, Germany.

Pathological conditions of the thyroid hormone (TH) system are routinely diagnosed by using serum concentrations of thyrotropin (TSH), which is sufficient in most cases. However, in certain conditions, such as resistance to TH due to mutations in (RTHb) or TSH-releasing pituitary adenoma (TSHoma), TSH may be insufficient for a correct diagnosis, even in combination with serum TH concentrations. Likewise, under TH replacement therapy, these parameters can be misleading and do not always allow optimal treatment. Hence, additional biomarkers to assess challenging clinical conditions would be highly beneficial. Data from untargeted multi-omics analyses of plasma samples from experimental thyrotoxicosis in human and mouse were exploited to identify proteins that might represent possible biomarkers of TH function. Subsequent mouse studies were used to identify the tissue of origin and the involvement of the two different TH receptors (TR). For in-depth characterization of the underlying cellular mechanisms, primary mouse cells were used. The analysis of the plasma proteome data sets revealed 16 plasma proteins that were concordantly differentially abundant under thyroxine treatment compared with euthyroid controls across the two species. These originated predominantly from liver, spleen, and bone. Independent studies in a clinical cohort and different mouse models identified CD5L as the most robust putative biomarker under different serum TH states and treatment periods. studies revealed that CD5L originates from proinflammatory M1 macrophages, which are similar to liver-residing Kupffer cells, and is regulated by an indirect mechanism requiring the secretion of a yet unknown factor from hepatocytes. In agreement with the role of TRα1 in immune cells and the TRβ-dependent hepatocyte-derived signaling, the regulation of expression depended on both TR isoforms. Our results identify several novel targets of TH action in serum, with CD5L as the most robust marker. Although further studies will be needed to validate the specificity of these targets, CD5L seems to be a promising candidate to assess TH action in hepatocyte-macrophage crosstalk.
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http://dx.doi.org/10.1089/thy.2019.0635DOI Listing
June 2020

Cholesterol and beyond - The role of the mevalonate pathway in cancer biology.

Biochim Biophys Acta Rev Cancer 2020 04 30;1873(2):188351. Epub 2020 Jan 30.

Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technische Universität Dresden, Germany; German Cancer Consortium (DKTK), partner site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany; Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany.

Cancer is a multifaceted global disease. Transformation of a normal to a malignant cell takes several steps, including somatic mutations, epigenetic alterations, metabolic reprogramming and loss of cell growth control. Recently, the mevalonate pathway has emerged as a crucial regulator of tumor biology and a potential therapeutic target. This pathway controls cholesterol production and posttranslational modifications of Rho-GTPases, both of which are linked to several key steps of tumor progression. Inhibitors of the mevalonate pathway induce pleiotropic antitumor-effects in several human malignancies, identifying the pathway as an attractive candidate for novel therapies. In this review, we will provide an overview about the role and regulation of the mevalonate pathway in certain aspects of cancer initiation and progression and its potential for therapeutic intervention in oncology.
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http://dx.doi.org/10.1016/j.bbcan.2020.188351DOI Listing
April 2020

Thyroid Hormone Actions and Bone Remodeling - The Role of the Wnt Signaling Pathway.

Exp Clin Endocrinol Diabetes 2020 Jun 20;128(6-07):450-454. Epub 2020 Jan 20.

Department of Medicine III and Center for Healthy Aging, Technische Universität Dresden, Germany.

Thyroid hormones are indispensable for bone development and growth. Also in adults, bone mass maintenance is under the control of thyroid hormones. Preclinical and clinical studies established untreated hyperthyroidism as a cause for secondary osteoporosis with increased fracture risk. Thus, normal thyroid function is essential for bone health. Mechanistically, thyroid hormone excess accelerates bone turnover with predominant bone resorption. How thyroid hormones affect osteoblast and osteoclast functions, however, still remains ill-defined. The Wnt signaling pathway is a major determinant of bone mass and strength as it promotes osteoblastogenesis and bone formation, while inhibiting bone resorption. So far, only few studies investigated a possible link between thyroid hormones, bone metabolism and the Wnt pathway. In this review, we summarize the literature linking thyroid hormones to bone homeostasis through Wnt signaling and discuss its potential as a therapeutic approach to treat hyperthyroidism-induced bone loss.
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http://dx.doi.org/10.1055/a-1088-1215DOI Listing
June 2020

Loss of Dkk-1 in Osteocytes Mitigates Alveolar Bone Loss in Mice With Periodontitis.

Front Immunol 2019 10;10:2924. Epub 2019 Dec 10.

Division of Endocrinology, Diabetes and Bone Diseases, Department of Medicine III & Center for Healthy Aging, Technical University, Dresden, Germany.

Periodontitis is a highly prevalent infection-triggered inflammatory disease that results in bone loss. Inflammation causes bone resorption by osteoclasts, and also by suppression of bone formation via increase of Dickkopf-1 (Dkk-1), an inhibitor of Wnt signaling. Here, we tested the hypothesis that osteocytic Dkk-1 is a key factor in the pathogenesis of periodontitis-induced alveolar bone loss (ABL). Twelve-week-old female mice with a constitutive deletion of Dkk-1 specifically in osteocytes (Dkk-1;Dmp1:Cre) were subjected to experimental periodontitis (EP). Cre-negative littermates served as controls. EP was induced by placing a ligature around the upper 2nd left molar, the contralateral side was used as control. Mice were killed after 11 days and maxillae removed for micro-CT and histological analyses. The mRNA expression of Dkk-1, Runx2, Osteocalcin, OPG, RANKL, RANKL/OPG ratio, LEF-1, and TCF-7 were assessed in maxillae, while mRNA expressions of TNF and IL-1 were evaluated on gingiva using real-time PCR. Blood samples were collected for Dkk-1, CTX, and P1NP measurement by ELISA. The deletion of Dkk-1 in osteocytes prevented ABL in mice with EP, compared to Cre-negative control mice with EP. Micro-CT analysis showed a significant reduction of bone loss (-28.5%) in EP Dkk-1;Dmp1:Cre-positive mice compared to their littermate controls. These mice showed a greater alveolar bone volume, bone mineral density, trabecular number, and trabecular thickness after EP when compared to the Cre-negative controls. The local expression in maxillae as well as the serum levels of Dkk-1 were reduced in Dkk-1;Dmp1:Cre-positive mice with EP. The transgenic mice submitted to EP showed increase of P1NP and reduction of CTX-I serum levels, and increase of TCF-7 expression. Histological analysis displayed less inflammatory infiltrates, a reduction of TNF and IL-1 expressions in the gingiva and fewer osteoclasts in Cre-positive animals with EP. Moreover, in mice with EP, the osteocytic deletion of Dkk-1 enhanced bone formation due to increased expressions of Runx2 and Osteocalcin and decreased expression of RANKL in maxillae. In summary, Dkk-1 derived from osteocytes plays a crucial role in ABL in periodontitis.
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http://dx.doi.org/10.3389/fimmu.2019.02924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6914827PMC
November 2020