scholarly journals Early-Onset Type 2 Diabetes Impairs Skeletal Acquisition in the Male TALLYHO/JngJ Mouse

Endocrinology ◽  
2014 ◽  
Vol 155 (10) ◽  
pp. 3806-3816 ◽  
Author(s):  
M. J. Devlin ◽  
M. Van Vliet ◽  
K. Motyl ◽  
L. Karim ◽  
D. J. Brooks ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Bone Marrow ◽  
Bone Mass ◽  
Early Onset ◽  
Volume Fraction ◽  
Mineral Density ◽  
Bone Volume Fraction ◽  
Skeletal Acquisition

Abstract Type 2 diabetes (T2D) incidence in adolescents is rising and may interfere with peak bone mass acquisition. We tested the effects of early-onset T2D on bone mass, microarchitecture, and strength in the TALLYHO/JngJ mouse, which develops T2D by 8 weeks of age. We assessed metabolism and skeletal acquisition in male TALLYHO/JngJ and SWR/J controls (n = 8–10/group) from 4 weeks to 8 and 17 weeks of age. Tallyho mice were obese; had an approximately 2-fold higher leptin and percentage body fat; and had lower bone mineral density vs SWR at all time points (P < .03 for all). Tallyho had severe deficits in distal femur trabecular bone volume fraction (−54%), trabecular number (−27%), and connectivity density (−82%) (P < .01 for all). Bone formation was higher in Tallyho mice at 8 weeks but lower by 17 weeks of age vs SWR despite similar numbers of osteoblasts. Bone marrow adiposity was 7- to 50-fold higher in Tallyho vs SWR. In vitro, primary bone marrow stromal cell differentiation into osteoblast and adipocyte lineages was similar in SWR and Tallyho, suggesting skeletal deficits were not due to intrinsic defects in Tallyho bone-forming cells. These data suggest the Tallyho mouse might be a useful model to study the skeletal effects of adolescent T2D.

scholarly journals Kindlin-2 regulates skeletal homeostasis by modulating PTH1R in mice

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Xuekun Fu ◽  
Bo Zhou ◽  
Qinnan Yan ◽  
Chu Tao ◽  
Lei Qin ◽  
...  
Keyword(s):  
Bone Mass ◽  
Volume Fraction ◽  
Bone Marrow Cells ◽  
Bone Matrix ◽  
Osteoblastic Cells ◽  
Mineral Density ◽  
Bone Volume Fraction ◽  
Ovariectomized Mice

AbstractIn vertebrates, the type 1 parathyroid hormone receptor (PTH1R) is a critical regulator of skeletal development and homeostasis; however, how it is modulated is incompletely understood. Here we report that deleting Kindlin-2 in osteoblastic cells using the mouse 10-kb Dmp1-Cre largely neutralizes the intermittent PTH-stimulated increasing of bone volume fraction and bone mineral density by impairing both osteoblast and osteoclast formation in murine adult bone. Single-cell profiling reveals that Kindlin-2 loss increases the proportion of osteoblasts, but not mesenchymal stem cells, chondrocytes and fibroblasts, in non-hematopoietic bone marrow cells, with concomitant depletion of osteoblasts on the bone surfaces, especially those stimulated by PTH. Furthermore, haploinsufficiency of Kindlin-2 and Pth1r genes, but not that of either gene, in mice significantly decreases basal and, to a larger extent, PTH-stimulated bone mass, supporting the notion that both factors function in the same genetic pathway. Mechanistically, Kindlin-2 interacts with the C-terminal cytoplasmic domain of PTH1R via aa 474–475 and Gsα. Kindlin-2 loss suppresses PTH induction of cAMP production and CREB phosphorylation in cultured osteoblasts and in bone. Interestingly, PTH promotes Kindlin-2 expression in vitro and in vivo, thus creating a positive feedback regulatory loop. Finally, estrogen deficiency induced by ovariectomy drastically decreases expression of Kindlin-2 protein in osteocytes embedded in the bone matrix and Kindlin-2 loss essentially abolishes the PTH anabolic activity in bone in ovariectomized mice. Thus, we demonstrate that Kindlin-2 functions as an intrinsic component of the PTH1R signaling pathway in osteoblastic cells to regulate bone mass accrual and homeostasis.

scholarly journals Estrogen Stimulation of Pleiotrophin Enhances Osteoblast Differentiation and Maintains Bone Mass in IGFBP-2 Null Mice

Endocrinology ◽  
2020 ◽  
Vol 161 (4) ◽  
Author(s):  
Gang Xi ◽  
Victoria E Demambro ◽  
Susan D’Costa ◽  
Shalier K Xia ◽  
Zach C Cox ◽  
...  
Keyword(s):  
Bone Mass ◽  
Osteoblast Differentiation ◽  
Volume Fraction ◽  
Tyrosine Phosphatase ◽  
Areal Bone Mineral Density ◽  
Wild Type ◽  
Mineral Density ◽  
Bone Volume Fraction ◽  
Skeletal Phenotype

Abstract Insulin-like growth factor binding protein-2 (IGFBP-2) stimulates osteoblast differentiation but only male Igfbp2 null mice have a skeletal phenotype. The trophic actions of IGFBP-2 in bone are mediated through its binding to receptor tyrosine phosphatase beta (RPTPβ). Another important ligand for RPTPβ is pleiotrophin (PTN), which also stimulates osteoblast differentiation. We determined the change in PTN and RPTPβ in Igfbp2–/– mice. Analysis of whole bone mRNA in wild-type and knockout mice revealed increased expression of Ptn. Rptpβ increased in gene-deleted animals with females having greater expression than males. Knockdown of PTN expression in osteoblasts in vitro inhibited differentiation, and addition of PTN to the incubation medium rescued the response. Estradiol stimulated PTN secretion and PTN knockdown blocked estradiol-stimulated differentiation. PTN addition to IGFBP-2 silenced osteoblast stimulated differentiation, and an anti-fibronectin-3 antibody, which inhibits PTN binding to RPTPβ, inhibited this response. Estrogen stimulated PTN secretion and downstream signaling in the IGFBP-2 silenced osteoblasts and these effects were inhibited with anti-fibronectin-3. Administration of estrogen to wild-type and Igfbp2–/– male mice stimulated an increase in both areal bone mineral density and trabecular bone volume fraction but the increase was significantly greater in the Igfbp2–/– animals. Estrogen also stimulated RPTPβ expression in the null mice. We conclude that loss of IGFBP-2 expression is accompanied by upregulation of PTN and RPTPβ expression in osteoblasts, that the degree of increase is greater in females due to estrogen secretion, and that this compensatory change may account for some component of the maintenance of normal bone mass in female mice.

scholarly journals Experimental Type 2 Diabetes Differently Impacts on the Select Functions of Bone Marrow-Derived Multipotent Stromal Cells

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 268
Author(s):  
Jonathan Ribot ◽  
Cyprien Denoeud ◽  
Guilhem Frescaline ◽  
Rebecca Landon ◽  
Hervé Petite ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Bone Marrow ◽  
Stromal Cells ◽  
Adipogenic Differentiation ◽  
Therapeutic Modality ◽  
Multipotent Stromal Cells ◽  
Cell Therapies

Bone marrow-derived multipotent stromal cells (BMMSCs) represent an attractive therapeutic modality for cell therapy in type 2 diabetes mellitus (T2DM)-associated complications. T2DM changes the bone marrow environment; however, its effects on BMMSC properties remain unclear. The present study aimed at investigating select functions and differentiation of BMMSCs harvested from the T2DM microenvironment as potential candidates for regenerative medicine. BMMSCs were obtained from Zucker diabetic fatty (ZDF; an obese-T2DM model) rats and their lean littermates (ZL; controls), and cultured under normoglycemic conditions. The BMMSCs derived from ZDF animals were fewer in number, with limited clonogenicity (by 2-fold), adhesion (by 2.9-fold), proliferation (by 50%), migration capability (by 25%), and increased apoptosis rate (by 2.5-fold) compared to their ZL counterparts. Compared to the cultured ZL-BMMSCs, the ZDF-BMMSCs exhibited (i) enhanced adipogenic differentiation (increased number of lipid droplets by 2-fold; upregulation of the Pparg, AdipoQ, and Fabp genes), possibly due to having been primed to undergo such differentiation in vivo prior to cell isolation, and (ii) different angiogenesis-related gene expression in vitro and decreased proangiogenic potential after transplantation in nude mice. These results provided evidence that the T2DM environment impairs BMMSC expansion and select functions pertinent to their efficacy when used in autologous cell therapies.

scholarly journals Genetics and Clinical Characteristics of PPARγ Variant-Induced Diabetes in a Chinese Han Population

2021 ◽  
Vol 12 ◽  
Author(s):  
Siqian Gong ◽  
Xueyao Han ◽  
Meng Li ◽  
Xiaoling Cai ◽  
Wei Liu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Early Onset ◽  
Rare Variants ◽  
Good Choice ◽  
Chinese Patients ◽  
Chinese Han ◽  
Diabetes Group ◽  
Onset Type

ObjectivesPPARγ variants cause lipodystrophy, insulin resistance, and diabetes. This study aimed to determine the relationship between PPARγ genotypes and phenotypes and to explore the pathogenesis of diabetes beyond this relationship.MethodsPPARγ2 exons in 1,002 Chinese patients with early-onset type 2 diabetes (diagnosed before 40 years of age) were sequenced. The functions of variants were evaluated by in vitro assays. Additionally, a review of the literature was performed to obtain all reported cases with rare PPARγ2 variants to evaluate the characteristics of variants in different functional domains.ResultsSix (0.6%) patients had PPARγ2 variant-induced diabetes (PPARG-DM) in the early-onset type 2 diabetes group, including three with the p.Tyr95Cys variant in activation function 1 domain (AF1), of which five patients (83%) had diabetic kidney disease (DKD). Functional experiments showed that p.Tyr95Cys suppresses 3T3-L1 preadipocyte differentiation. A total of 64 cases with damaging rare variants were reported previously. Patients with rare PPARγ2 variants in AF1 of PPARγ2 had a lower risk of lipodystrophy and a higher rate of obesity than those with variants in other domains, as confirmed in patients identified in this study.ConclusionThe prevalence of PPARG-DM is similar in Caucasian and Chinese populations, and DKD was often observed in these patients. Patients with variants in the AF1 of PPARγ2 had milder clinical phenotypes and lack typical lipodystrophy features than those with variants in other domains. Our findings emphasize the importance of screening such patients via genetic testing and suggest that thiazolidinediones might be a good choice for these patients.

scholarly journals Bone Mass and Density in Youth with Type 2 Diabetes, Obesity, and Healthy Weight

2020 ◽  
Author(s):  
Joseph M. Kindler ◽  
Andrea Kelly ◽  
Philip R. Khoury ◽  
Lorraine E. Levitt Katz ◽  
Elaine M. Urbina ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Bone Mass ◽  
Fracture Risk ◽  
Visceral Fat ◽  
Whole Body ◽  
Areal Bone Mineral Density ◽  
Healthy Weight ◽  
Mineral Density ◽  
Z Scores

<b>Objective</b>: Youth-onset type 2 diabetes is an aggressive condition with increasing incidence. Adults with type 2 diabetes have increased fracture risk despite normal areal bone mineral density (aBMD), but the influence of diabetes on the growing skeleton is unknown. We compared bone health in youth with type 2 diabetes to controls with obesity or healthy weight. <p><b>Research Design and Methods</b>: Cross-sectional study of youth (56% African American, 67% female) ages 10-23 years with type 2 diabetes (n=180), obesity (BMI>95<sup>th</sup>; n=226), or healthy weight (BMI<85<sup>th</sup>; n=238). Whole body (less head) aBMD and lean mass, and abdominal visceral fat were assessed via DXA. Lean body mass index (LBMI) and aBMD standard deviation (SD) scores (“Z-scores”) were computed using published reference data. </p> <p><b>Results</b>: We observed age-dependent differences in aBMD and LBMI Z-scores between the healthy weight, obese, and type 2 diabetes groups. In children, aBMD and LBMI Z-scores were greater in the type 2 diabetes vs obese groups, but in adolescents and young adults, aBMD and LBMI Z-scores were lower in the type 2 diabetes vs. obese group (age interactions P<0.05). In the type 2 diabetes and obese groups, aBMD was about 0.5 SDs lower for a given LBMI Z-score compared to healthy weight controls (P<0.05). Further, aBMD was lower in those with greater visceral fat (β=-0.121, P=0.047).</p> <p><b>Conclusions</b>: These results suggest that type 2 diabetes may be detrimental to bone density around the age of peak bone mass. Given the increased fracture risk in adults with type 2 diabetes, there is a pressing need for longitudinal studies aimed at understanding the influence of diabetes on the growing skeleton.</p>

scholarly journals Osteoporosis, Fractures, and Diabetes

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Peter Jackuliak ◽  
Juraj Payer
Keyword(s):  
Bone Mineral Density ◽  
Type 2 Diabetes ◽  
Bone Mass ◽  
Bone Mineral ◽  
Bone Fractures ◽  
Trabecular Bone Score ◽  
Bone Fragility ◽  
Mineral Density ◽  
Increased Risk

It is well established that osteoporosis and diabetes are prevalent diseases with significant associated morbidity and mortality. Patients with diabetes mellitus have an increased risk of bone fractures. In type 1 diabetes, the risk is increased by ∼6 times and is due to low bone mass. Despite increased bone mineral density (BMD), in patients with type 2 diabetes the risk is increased (which is about twice the risk in the general population) due to the inferior quality of bone. Bone fragility in type 2 diabetes, which is not reflected by bone mineral density, depends on bone quality deterioration rather than bone mass reduction. Thus, surrogate markers and examination methods are needed to replace the insensitivity of BMD in assessing fracture risks of T2DM patients. One of these methods can be trabecular bone score. The aim of the paper is to present the present state of scientific knowledge about the osteoporosis risk in diabetic patient. The review also discusses the possibility of problematic using the study conclusions in real clinical practice.

Healing Cranial Defects with AdRunx2-transduced Marrow Stromal Cells

2007 ◽  
Vol 86 (12) ◽  
pp. 1207-1211 ◽  
Author(s):  
Z. Zhao ◽  
Z. Wang ◽  
C. Ge ◽  
P. Krebsbach ◽  
R.T. Franceschi
Keyword(s):  
Stromal Cells ◽  
Volume Fraction ◽  
Marrow Stromal Cells ◽  
Osteogenic Potential ◽  
Specific Gene ◽  
Mineral Density ◽  
Bone Volume Fraction ◽  
Calvarial Defects

Marrow stromal cells (MSCs) include stem cells capable of forming all mesenchymal tissues, including bone. However, before MSCs can be successfully used in regeneration procedures, methods must be developed to stimulate their differentiation selectively to osteoblasts. Runx2, a bone-specific transcription factor, is known to stimulate osteoblast differentiation. In the present study, we tested the hypothesis that Runx2 gene therapy can be used to heal a critical-sized defect in mouse calvaria. Runx2-engineered MSCs displayed enhanced osteogenic potential and osteoblast-specific gene expression in vitro and in vivo. Runx2-expressing cells also dramatically enhanced the healing of critical-sized calvarial defects and increased both bone volume fraction and bone mineral density. These studies provide a novel route for enhancing osteogenesis that may have future therapeutic applications for craniofacial bone regeneration.

scholarly journals Bone Mass and Density in Youth with Type 2 Diabetes, Obesity, and Healthy Weight

2020 ◽  
Author(s):  
Joseph M. Kindler ◽  
Andrea Kelly ◽  
Philip R. Khoury ◽  
Lorraine E. Levitt Katz ◽  
Elaine M. Urbina ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Bone Mass ◽  
Fracture Risk ◽  
Visceral Fat ◽  
Whole Body ◽  
Areal Bone Mineral Density ◽  
Healthy Weight ◽  
Mineral Density ◽  
Z Scores

<b>Objective</b>: Youth-onset type 2 diabetes is an aggressive condition with increasing incidence. Adults with type 2 diabetes have increased fracture risk despite normal areal bone mineral density (aBMD), but the influence of diabetes on the growing skeleton is unknown. We compared bone health in youth with type 2 diabetes to controls with obesity or healthy weight. <p><b>Research Design and Methods</b>: Cross-sectional study of youth (56% African American, 67% female) ages 10-23 years with type 2 diabetes (n=180), obesity (BMI>95<sup>th</sup>; n=226), or healthy weight (BMI<85<sup>th</sup>; n=238). Whole body (less head) aBMD and lean mass, and abdominal visceral fat were assessed via DXA. Lean body mass index (LBMI) and aBMD standard deviation (SD) scores (“Z-scores”) were computed using published reference data. </p> <p><b>Results</b>: We observed age-dependent differences in aBMD and LBMI Z-scores between the healthy weight, obese, and type 2 diabetes groups. In children, aBMD and LBMI Z-scores were greater in the type 2 diabetes vs obese groups, but in adolescents and young adults, aBMD and LBMI Z-scores were lower in the type 2 diabetes vs. obese group (age interactions P<0.05). In the type 2 diabetes and obese groups, aBMD was about 0.5 SDs lower for a given LBMI Z-score compared to healthy weight controls (P<0.05). Further, aBMD was lower in those with greater visceral fat (β=-0.121, P=0.047).</p> <p><b>Conclusions</b>: These results suggest that type 2 diabetes may be detrimental to bone density around the age of peak bone mass. Given the increased fracture risk in adults with type 2 diabetes, there is a pressing need for longitudinal studies aimed at understanding the influence of diabetes on the growing skeleton.</p>

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