Dong-mei Liu

Glucagon-like peptide-1 receptor agonist Liraglutide has anabolic bone effects in ovariectomized rats without diabetes.

Recently, a number of studies have demonstrated the potential beneficial role for novel anti-diabetic GLP-1 receptor agonists (GLP-1RAs) in the skeleton metabolism in diabetic rodents and patients. In this study, we evaluated the impacts of the synthetic GLP-1RA Liraglutide on bone mass and quality in osteoporotic rats induced by ovariectomy (OVX) but without diabetes, as well as its effect on the adipogenic and osteoblastogenic differentiation of bone marrow stromal cells (BMSCs). Three months after sham surgery or bilateral OVX, eighteen 5-month old female Wistar rats were randomly divided into three groups to receive the following treatments for 2 months: (1) Sham + normal saline; (2) OVX + normal saline; and (3) OVX + Liraglutide (0.6 mg/day). As revealed by micro-CT analysis, Liraglutide improved trabecular volume, thickness and number, increased BMD, and reduced trabecular spacing in the femurs in OVX rats; similar results were observed in the lumbar vertebrae of OVX rats treated with Liraglutide. Following in vitro treatment of rat and human BMSCs with 10 nM Liraglutide, there was a significant increase in the mRNA expression of osteoblast-specific transcriptional factor Runx2 and the osteoblast markers alkaline phosphatase (ALP) and collagen α1 (Col-1), but a significant decrease in peroxisome proliferator-activated receptor γ (PPARγ). In conclusion, our results indicate that the anti-diabetic drug Liraglutide can exert a bone protective effect even in non-diabetic osteoporotic OVX rats. This protective effect is likely attributable to the impact of Liraglutide on the lineage fate determination of BMSCs.

PROTECTIVE EFFECTS OF BONE MORPHOGENETIC PROTEIN 7 AGAINST AMYLOID-BETA INDUCED NEUROTOXICITY IN PC12 CELLS

Bone morphogenetic protein 7 (BMP7) has neuroprotective effects against ischemia, oxidation stress, and lipopolysaccharide, but its role on amyloid-beta (Aβ)-induced neurotoxicity in Alzheimers disease (AD) and the underlying mechanisms remain unclear. In this study, we exposed PC12 cells to Aβ25-35 for 26 h to induce neurotoxicity, and added exogenous BMP7 at 2 h to observe the neuroprotective effects. The protective mechanisms involved, mostly related to inhibition of cell apoptosis and oxidation stress, were analyzed. In rat in vivo experiments, we bilaterally injected Aβ1-40 into the basal forebrain to simulate neuropathological processes in AD, performed the Morris water maze test to evaluate the effect of Aβ on spatial learning and memory, and explored the change of endogenous BMP7 expression in the brain. The present study demonstrated that BMP7 prevented neuronal injuries in PC12 cells induced by Aβ25-35, including cell apoptosis and morphological impairment of dendrites as well as oxidation stress. BMP7 treatment significantly protected PC12 cells against Aβ25-35-induced injury and inhibited the increasing content of the Bax gene and the decreasing activities of superoxide dismutase (SOD). Aβ1-40 bilaterally injected into the rat basal forebrain obviously inhibited the rats spatial learning ability and memory, and significantly induced downregulation of endogenous BMP7 in the basal forebrain while upregulating it in the hippocampus. Our results suggest that BMP7 has neuroprotective effects against Aβ, which may be mediated through inhibition of Bax gene expression during cell apoptosis and elevation of SOD activities during the oxidative stress response. On the other hand, endogenous BMP7 may have a potential self-modulation capacity through negative feedback between the region of the basal forebrain and the hippocampus as a protective cytokine.

Positive Association Between Serum Levels of Bone Resorption Marker CTX and HbA1c in Women With Normal Glucose Tolerance

CONTEXT The bone formation marker osteocalcin (OCN) has a beneficial effect on glucose metabolism. In mice, the OCN bioactivity is induced by bone resorption. But in humans, the role of bone resorption in modulating glucose homeostasis is not clear. OBJECTIVE Our study aimed to examine the relationship between bone resorption and glucose homeostasis in humans. DESIGN AND SETTING This was a cross-sectional study conducted in a university teaching hospital. SUBJECTS A total of 195 women with normal glucose tolerance (NGT) were analyzed. MAIN OUTCOME MEASURES Serum OCN, cross-linked C-telopeptide of type I collagen (CTX), fasting plasma glucose, and 2h post-challenge glucose levels during oral glucose tolerance test, fasting insulin, glycated hemoglobin A1c (HbA1c), hepatic and renal functions, electrolytes, and bone mineral densities (BMDs) at lumbar-spine and proximal femur, and anthropometric parameters were measured. RESULTS CTX was positively associated with HbA1c after adjustments for multiple confounding factors (r = 0.269, P = .006). OCN (β = 0.015, P = .000), lumbar-spine 2-4 (L2-4) BMD (β = -0.128, P = .003) and HbA1c (β = 0.051, P = .01) were the major determinants of the variations of CTX (adjusted R(2) for the model = 0.608, P = .01) based on multivariate regression analysis. Compared with those in the lowest HbA1c tertile, individuals in the highest tertile had significantly higher CTX concentrations (0.37 ± 0.15 ng/ml vs 0.26 ± 0.11 ng/ml, P = .000), even when multiple confounders were adjusted (P for trend = .015). CONCLUSIONS Bone resorption marker serum CTX was independently associated HbA1c in NGT women. Whether the increased CTX level in NGT subjects is an early marker predicting the subtle impairment of glucose homeostasis and the risk of occurrence of diabetes requires additional study.

Serum Sema3A Is in a Weak Positive Association With Bone Formation Marker Osteocalcin But Not Related to Bone Mineral Densities in Postmenopausal Women

CONTEXT The chemorepellent semaphorin-3A (Sema3A) was shown to favor bone metabolism in mice, but its bone effects in humans are not described. OBJECTIVE The aim of the study was to investigate the associations between serum Sema3A, bone biochemical markers, and bone mineral densities (BMDs) in women. DESIGN, SETTING, AND PARTICIPANTS This was a cross-sectional study involving 1012 pre- and postmenopausal women. MAIN OUTCOME MEASURES Fasting serum Sema3A, osteocalcin (Ocn), and cross-linked C-telopeptide of type 1 collagen were measured. Dual-energy X-ray absorptiometry was performed to determine the BMDs at the lumbar spine and femoral neck. History of osteoporotic fractures was reported by the participants. RESULTS In postmenopausal women (n = 860), a significant positive association between Sema3A and Ocn levels was demonstrated (r = 0.077, P = 0.025) when age was adjusted. The serum Ocn level was significantly higher in the fourth quartile of serum Sema3A as compared with the first quartile (21.09 ± 0.56 ng/mL vs 19.45 ± 0.44 ng/mL, P = .018). Serum Sema3A concentrations were similar in subjects with normal BMD, osteopenia or osteoporosis, and those with and without osteoporotic fractures. Multivariate stepwise regression analysis revealed that cross-linked C-telopeptide of type 1 collagen, body mass index, creatinine, Sema3A, L1-4 BMDs, and age were determinants of Ocn (adjusted R(2) for the model = 0.532, P < .001) . CONCLUSIONS The positive correlation between Sema3A and bone formation marker Ocn revealed in this human study partly supports the recently findings in mice studies. However, the general effects of Sema3A on bone metabolism are weak and not clear as evidenced by lack of association between this parameter and BMDs and osteoporotic fractures.

The association between the baseline bone resorption marker CTX and incident dysglycemia after 4 years

Bone is an endocrine organ involved in modulating glucose homeostasis. The role of the bone formation marker osteocalcin (OCN) in predicting diabetes was reported, but with conflicting results. No study has explored the association between baseline bone resorption activity and incident diabetes or prediabetes during follow-up. Our objective was to examine the relationship between the baseline bone resorption marker crosslinked C-telopeptide of type I collagen (CTX) and glycemic dysregulation after 4 years. This longitudinal study was conducted in a university teaching hospital. A total of 195 normal glucose tolerant (NGT) women at baseline were invited for follow-up. The incidence of diabetes and prediabetes (collectively defined as dysglycemia) was recorded. A total of 128 individuals completed the 4-year study. The overall conversion rate from NGT to dysglycemia was 31.3%. The incidence of dysglycemia was lowest in the middle tertile [16.3% (95% confidence interval (CI), 6.8%–30.7%)] compared with the lower [31.0% (95% CI, 17.2%–46.1%)] and upper [46.5% (95% CI, 31.2%–62.6%)] tertiles of CTX, with a significant difference seen between the middle and upper tertiles (P=0.002 5). After adjusting for multiple confounding variables, the upper tertile of baseline CTX was associated with an increased risk of incident dysglycemia, with an odds ratio of 7.09 (95% CI, 1.73–28.99) when the middle tertile was the reference. Osteoclasts actively regulate glucose homeostasis in a biphasic model that moderately enhanced bone resorption marker CTX at baseline provides protective effects against the deterioration of glucose metabolism, whereas an overactive osteoclastic function contributes to an increased risk of subsequent dysglycemia.

Rictor/mTORC2 loss in osteoblasts impairs bone mass and strength

Mammalian target of rapamycin (mTOR) is a Ser/Thr kinase conserved through evolution that coordinates extra cellular signals associated with cell growth. Main functions of mTOR present in the form of two complexes, namely mTORC1 and mTORC2, which are distinct in their unique components, raptor and rictor. In the current study, using a Cre/loxp system, we found an anabolic effect of mTORC2 signaling on skeleton. Osteoblast differentiation was reduced, with down-regulation of mTORC2 signaling activity in primary cultures of osteoblasts that did not contain rictor. Mice with a specific deletion of rictor in mature osteoblasts showed a significant reduction in lean mass and bone mineral density by dual energy x-ray absorptiometry analysis. Micro-computed tomography, histomorphometric, and molecular biological analyses revealed a marked impairment of the cortical bone mass and microarchitecture, as well as minor changes in trabecular bone, of the Rictorob(-/-) mice. Cortical bone mass and thickness of the femoral mid-shaft were dramatically reduced, with unusual increases in porosity and marrow area in Rictorob(-/-) mice. Thinner trabeculae were found in the L4 vertebrae with relatively normal structural indices of trabecular numbers and separation. A lower rate of bone turnover was observed, as the consequence of the decreased individual osteoblast activity and bone resorption. Furthermore, these changes were associated with significantly decreased bone biomechanical properties. In conclusion, expression of rictor in osteoblasts is essential for the maintenance of normal bone remodeling and microarchitecture, especially for the maintenance of the cortical bone.

FGF18 protects against 6-hydroxydopamine-induced nigrostriatal damage in a rat model of Parkinson’s disease

Dopaminergic neuronal injury in the substantia nigra (SN) is a pathological hallmark of Parkinsons disease (PD). However, the underlying mechanism of this injury remains elusive. Since fibroblast growth factor 18 (FGF18) is involved in midbrain development and has been reported to protect neurons from ischemic injury, we investigated whether FGF18 exerted a protective effect on dopaminergic neurons in the SN. In vitro data showed that FGF18 significantly ameliorated the neurotoxicity of 6-hydroxydopamine (6-OHDA) through the AKT/GSK3β signaling pathway. Further study of the 6-OHDA-induced PD rat model indicated that FGF18 improved the behavioral dysfunction in PD rats and reduced the tyrosine hydroxylase (TH)-positive neuronal loss in the SN. In addition, 6-OHDA induced a loss of TH-positive fibers that was reversed by pretreatment with FGF18. Taken together, these data suggest that FGF18 plays a protective role against parkinsonian neurodegeneration in the nigrostriatal system in a 6-OHDA-induced PD rat model and that further drug discovery based on FGF18 has a potential role for PD therapy.