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Item type:Publication, Access status: with files , Update on the impact of type 2 diabetes mellitus on bone metabolism and material propertiesThe prevalence of type 2 diabetes mellitus (T2DM) is increasing worldwide, especially as a result of our aging society, high caloric intake and sedentary lifestyle. Besides the well-known complications of T2DM on the cardiovascular system, the eyes, kidneys and nerves, bone strength is also impaired in diabetic patients. Patients with T2DM have a 40–70% increased risk for fractures, despite having a normal to increased bone mineral density, suggesting that other factors besides bone quantity must account for increased bone fragility. This review summarizes the current knowledge on the complex effects of T2DM on bone including effects on bone cells, bone mat erial properties and other endocrine systems that subsequently affect bone, discusses the effects of T2DM medications on bone and concludes with a model identifying factors that may contribute to poor bone quality and increased bone fragility in T2DM. © 2019 The authors Published by Bioscientifica Ltd.Publicationtype: Journal ArticleScopus© Citations 85 375 501 - Some of the metrics are blocked by yourconsent settings
Item type:Publication, Access status: with files , Thy-1 deficiency augments bone loss in obesity by affecting bone formation and resorption(Frontiers Media S.A., 2018-10-02); ; ; ; Healthy bone remodeling results from a balanced bone formation and bone resorption realized by bone-forming osteoblasts and bone-resorbing osteoclasts, respectively. Recently, Thy-1 (CD90) was identified as positive regulator of osteoblast differentiation and activation, thus, promoting bone formation while concurrently inhibiting adipogenesis and obesity in mice. Additionally, Thy-1 did not affect bone resorption. An obesity-related co-morbidity that is increasing in prevalence is a disturbed bone formation resulting in an increased fracture risk. The underlying mechanisms of obesity-induced bone alterations are not yet fully elucidated and therefore therapy options for efficient bone-anabolic treatments are limited. Therefore, we investigated the impact of Thy-1 on bone metabolism under obese conditions. Indeed, high fat diet (HFD) induced obese mice lacking Thy-1 (Thy-1-/-) showed increased body fat mass compared to wildtype (WT) mice while bone mass (-38%) and formation (-57%) were decreased as shown by micro-computed tomography (μCT) measurement, histological analysis, and fourier-transform infrared spectroscopy (FTIR). Interestingly, under obese conditions, lack of Thy-1 affected both osteoblast and osteoclast function. Number (-30%) and activity of osteoblasts were decreased in obese Thy-1-/- mice while osteoclast number (+39%) and activity were increased. Facilitated bone marrow fat accumulation (+56%) in obese Thy-1-/- mice compared to obese WT mice was associated with upregulated tumor necrosis factor α (Tnfα, +46%) and colony stimulating factor 1 receptor (Csf1r) expression, strong promoters of osteoclast differentiation. Moreover, lack of Thy-1 was accompanied by a reduction of osteoprotegerin (Tnfrsf11b) expression (-36%), an inhibitor of osteoclast differentiation. Altered Tnfα, Csf1r, and Tnfrsf11b expression might be responsible for elevated osteoclast activity in obese Thy-1-deficient mice. In summary, our findings show that lack of Thy-1 promotes obesity under HFD conditions while concurrently decreasing bone mass and formation. Mechanistic studies revealed that under obese conditions lack of Thy-1 impairs both bone formation and bone resorption.Publicationtype: Journal ArticleScopus© Citations 14 350 401 - Some of the metrics are blocked by yourconsent settings
Item type:Publication, Access status: without files , Thy-1 (CD90) promotes bone formation and protects against obesityOsteoporosis and obesity result from disturbed osteogenic and adipogenic differentiation and present emerging challenges for our aging society. Because of the regulatory role of Thy-1 in mesenchyme-derived fibroblasts, we investigated the impact of Thy-1 expression on mesenchymal stem cell (MSC) fate between osteogenic and adipogenic differentiation and consequences for bone formation and adipose tissue development in vivo. MSCs from Thy-1-deficient mice have decreased osteoblast differentiation and increased adipogenic differentiation compared to MSCs from wild-type mice. Consistently, Thy-1-deficient mice exhibited decreased bone volume and bone formation rate with elevated cortical porosity, resulting in lower bone strength. In parallel, body weight, subcutaneous/epigonadal fat mass, and bone fat volume were increased. Thy-1 deficiency was accompanied by reduced expression of specific Wnt ligands with simultaneous increase of the Wnt inhibitors sclerostin and dickkopf-1 and an altered responsiveness to Wnt. We demonstrated that disturbed bone remodeling in osteoporosis and dysregulated adipose tissue accumulation in patients with obesity were mirrored by reduced serum Thy-1 concentrations. Our findings provide new insights into the mutual regulation of bone formation and obesity and open new perspectives to monitor and to interfere with the dysregulated balance of adipogenesis and osteogenesis in obesity and osteoporosis.Publicationtype: Journal Article132 - Some of the metrics are blocked by yourconsent settings
Item type:Publication, Access status: without files , Effects of insulin therapy on porosity, non-enzymatic glycation and mechanical competence in the bone of rats with type 2 diabetes mellitusType 2 diabetes mellitus increases skeletal fragility; however, the contributing mechanisms and optimal treatment strategies remain unclear. We studied the effects of diabetes and insulin therapy on non-enzymatic glycation (NEG), cortical porosity (Ct.Po) and biomechanics of the bone tissue in Zucker Diabetic Fatty (ZDF) rats. Eleven-week old ZDF diabetic and non-diabetic rats were given insulin to achieve glycaemic control or vehicle seven days per week over twelve weeks (insulin dose adapted individually 0.5 international units (IU) at week 1 to 13.0 IU at week 12). The right femora were excised, micro-CT scanned, and tested in 3-point bending to measure biomechanics. NEG of the midshaft was determined from bulk fluorescence. Diabetes led to increased NEG (+ 50.1%, p = 0.001) and Ct.Po (+ 22.9%, p = 0.004), as well as to reduced mechanical competence (max. stress: − 14.2%, p = 0.041, toughness: − 29.7%, p = 0.016) in the bone tissue. NEG and Ct.Po both correlated positively to serum glucose (NEG: R2 = 0.41, p < 0.001, Ct.Po: R2 = 0.34, p = 0.003) and HbA1c (NEG: R2 = 0.42, p < 0.001, Ct.Po: R2 = 0.28, p = 0.008) levels, while NEG correlated negatively with bone biomechanics (elastic modulus: R2 = 0.21, p = 0.023, yield stress: R2 = 0.17, p = 0.047). Twelve weeks of insulin therapy had no significant effect on NEG or Ct.Po, and was unable to improve the mechanical competence of the bone tissue. A reduction of mechanical competence was observed in the bone tissue of the diabetic rats, which was explained in part by increased collagen NEG. Twelve weeks of insulin therapy did not alter NEG, Ct.Po or bone biomechanics. However, significant correlations between NEG and serum glucose and HbA1c were observed, both of which were reduced with insulin therapy. This suggests that a longer duration of insulin therapy may be required to reduce the NEG of the bone collagen and restore the mechanical competence of diabetic bone.Publicationtype: Journal Article133 - Some of the metrics are blocked by yourconsent settings
Item type:Publication, Access status: without files , Effects of parathyroid hormone on cortical porosity, non-enzymatic glycation and bone tissue mechanics in rats with type 2 diabetes mellitusType 2 diabetes mellitus increases skeletal fragility; however, the contributing mechanisms and the efficacy of bone-forming agents are unclear. We studied diabetes and parathyroid hormone (PTH) treatment effects on cortical porosity (Ct.Po), non-enzymatic glycation (NEG) and bone mechanics in Zucker diabetic fatty (ZDF) rats.Eleven-week old ZDF diabetic (DB) and non-diabetic (ND) rats were given 75. μg/kg PTH (1-84) or vehicle 5. days per week over 12. weeks. The right femora and L4 vertebrae were excised, micro-CT scanned, and tested in 3-point bending and uniaxial compression, respectively. NEG of the samples was determined using fluorescence.Diabetes increased Ct.Po (vertebra (vert): + 40.6%, femur (fem): + 15.5% vs. ND group, p < 0.05) but had no effect on NEG. PTH therapy reduced vertebral NEG in the ND animals only (- 73% vs untreated group, p < 0.05), and increased femoral NEG in the DB vs. ND groups (+ 63%, p < 0.05). PTH therapy had no effect on Ct.Po. Diabetes negatively affected bone tissue mechanics where reductions in vertebral maximum strain (- 22%) and toughness (- 42%) were observed in the DB vs. ND group (p < 0.05). PTH improved maximum strain in the vertebra of the ND animals (+ 21%, p < 0.05) but did not have an effect in the DB group. PTH increased femoral maximum strain (+ 21%) and toughness (+ 28%) in ND and decreased femoral maximum stress (- 13%) and toughness (- 27%) in the DB animals (treated vs. untreated, p < 0.05). Ct.Po correlated negatively with maximum stress (fem: R = - 0.35, p < 0.05, vert: R = - 0.57, p. < 0.01), maximum strain (fem: R = - 0.35, p. <. 0.05, vert: R. = - 0.43, p. < 0.05) and toughness (fem: R = - 0.34, p < 0.05, vert: R = - 0.55, p < 0.01), and NEG correlated negatively with toughness at the femur (R = - 0.34, p < 0.05) and maximum strain at the vertebra (R = - 0.49, p < 0.05).Diabetes increased cortical porosity and reduced bone mechanics, which were not improved with PTH treatment. PTH therapy alone may worsen diabetic bone mechanics through formation of new bone with high AGEs cross-linking. Optimal treatment regimens must address both improvements of bone mass and glycemic control in order to successfully reduce diabetic bone fragility.This article is part of a Special Issue entitled "Bone and diabetes".Publicationtype: Journal Article155 - Some of the metrics are blocked by yourconsent settings
Item type:Publication, Access status: without files , Effects of parathyroid hormone on bone mass, bone strength, and bone regeneration in male rats with type 2 diabetes mellitus(2014-04-01); ; 10