Diabetic Osteoporosis Research Articles

Effect of Liraglutide on Osteoporosis in a Rat Model of Type 2 Diabetes Mellitus: A Histological, Immunohistochemical, and Biochemical Study.

Diabetic osteoporosis (DOP) is a diabetic complication associated with a significant disability rate. Liraglutide, a glucagon-like peptide-1 receptor agonist, is a promising and innovative drug for type 2 diabetes mellitus (T2DM), with potential therapeutic implications for bone disorders. This investigation examined the impact of liraglutide on osteoporosis in rats with T2DM and studied the influence of vitamin D receptor Bsm1 polymorphism on liraglutide-induced outcomes. Thirty rats were divided into control, T2DM induced by a combination of a high-fat diet and 25 mg/kg streptozotocin, and T2DM-liraglutide (T2DM treated with 0.4 mg/kg/day liraglutide) groups. After 8 weeks of liraglutide treatment, femurs and blood samples were obtained from all rats for subsequent investigations. Diabetes induced a remarkable rise in the serum levels of receptor activator of nuclear factor kappa B ligand (RANKL) and C-telopeptide of type I collagen (CTX-1) associated with a remarkable decline in osteocalcin and osteoprotegerin (OPG). Impaired bone architecture was also demonstrated by light and scanning electron microscopic study. The immune expression of OPG was down-regulated, while RANKL was up-regulated. Interestingly, the administration of liraglutide ameliorated the previous changes induced by diabetes mellitus. In conclusion, liraglutide can prevent DOP, mostly due to liraglutide's ability to increase bone growth, while inhibiting bone resorption.

Understanding the mechanisms and implications of acacetin in mitigating diabetic osteoporosis: Insights from a zebrafish model

Osteoporosis, a condition characterised by reduced bone mineral density is more prevalent in individuals with diabetes. Acacetin, a natural flavonoid, possesses anti-inflammatory and antioxidant properties. However, its protective role in diabetic osteoporosis remains unexplored. Hence, the present study aimed to investigate the antihyperglycemic, antioxidant, and osteoprotective effects of acacetin using streptozotocin (STZ)-induced diabetic osteoporosis models in larval and adult zebrafish. The larvae were subjected to assays such as embryotoxicity, detection of oxidative stress markers (reactive oxygen species (ROS), superoxide levels, lipid peroxidation), apoptosis, and gene expression related to diabetes and osteoporosis. In adult zebrafish, body weight, blood glucose level, alkaline phosphatase, and tartrate resistant acid phosphatase (TRAP) activity were estimated, along with assays like alizarin red staining, histopathology, and gene expression. Interaction of acacetin and RANK/RANKL/OPG pathway was detected using molecular docking analysis. Acacetin exhibited antihyperglycemic effects in the zebrafish model, as shown by reduced blood glucose levels and increased body weight. Acacetin also demonstrated antioxidant properties by decreasing ROS, superoxide radicals, and lipid peroxidation levels. Additionally, acacetin treatment resulted in reduction of apoptosis and tartrate-resistant acid phosphatase levels and improved bone histology with increased bone density and enhanced alkaline phosphatase activity. In gene expression analysis, acacetin treatment has upregulated osteoprotegerin gene and downregulated RANKL gene. In conclusion, acacetin holds potential as a therapeutic agent for diabetic osteoporosis by targeting hyperglycemia, oxidative stress, apoptosis, and the RANK/RANKL/OPG signalling pathway.

Acid sphingomyelinase mediates ferroptosis induced by high glucose via autophagic degradation of GPX4 in type 2 diabetic osteoporosis

BackgroundFerroptosis has been implicated in the pathological process of type 2 diabetic osteoporosis (T2DOP), although the specific underlying mechanisms remain largely unknown. This study aimed to clarify the role and possible mechanism of acid sphingomyelinase (ASM)-mediated osteoblast ferroptosis in T2DOP.MethodsWe treated hFob1.19 cells with normal glucose (NG) and different concentrations of high glucose (HG, 26.25 mM, 35 mM, or 43.75 mM) for 48 h. We then measured cell viability and osteogenic function, quantified ferroptosis and autophagy levels, and measured the levels of ASM and ceramide in the cells. To further investigate the specific mechanism, we examined these indicators by knocking down ASM expression, hydroxychloroquine (HCQ) treatment, or N-acetylcysteine (NAC) treatment. Moreover, a T2DOP rat model was induced and microcomputed tomography was used to observe the bone microstructure. We also evaluated the serum levels of iron metabolism-associated factors, ceramide and lipid peroxidation (LPO) and measured the expression of ASM, LC3 and GPX4 in bone tissues.ResultsHG inhibited the viability and osteogenic function of osteoblasts by inducing ferroptosis in a concentration-dependent manner. Furthermore, the expression of ASM and ceramide and autophagy levels were increased by HG treatment, and these factors were required for the HG-induced reactive oxygen species (ROS) generation and LPO. Similarly, inhibiting intracellular ROS also reduced HG-induced ASM activation and autophagy. ASM-mediated activation of autophagy was crucial for HG-induced degradation of GPX4, and inhibiting ASM improved osteogenic function by decreasing HG-induced autophagy, GPX4 degradation, LPO and subsequent ferroptosis. We also found that inhibiting ASM could alleviated ferroptosis and autophagy and improved osteogenic function in a T2DOP rat model.ConclusionASM-mediated autophagy activation induces osteoblast ferroptosis under HG conditions through the degradation of GPX4, providing a novel mechanistic insight into the treatment and prevention of T2DOP.

Suppression of TLR4 prevents diabetic bone loss by regulating FTO-mediated m6A modification.

Toll-like receptor-4 (TLR4) has been implicated in the development and progression of diabetic osteoporosis. However, the mechanisms underlying TLR4-regulated bone metabolism in diabetes are yet to be fully understood. Epigenetic modifications have been indicated as a possible mechanism leading to increased risk of osteoporosis and bone fracture. As N6-methyladenosine (m6A) is the most common epigenetic modification in eukaryotic mRNAs, we hypothesized that TLR4 regulates m6A modification in bone tissues of diabetic rats, thereby potentially explaining the pathogenesis of diabetic bone loss. m6A sequencing (m6A-seq) was performed in samples of the femur of TLR4-wild type (TLR4WT) and TLR4-knockout (TLR4KO) diabetic rats to identify genes with differential m6A modifications that may be associated with the bone loss phenotype. We found that in TLR4KO rats, the rapid weight loss of diabetic rats was prevented, and bone mineral density (BMD) was significantly increased. m6A-seq and Gene Ontology enrichment analysis revealed that m6A-modified genes in the femur of TLR4KO diabetic rats were associated with regulation of biological processes such as osteoclast differentiation. qRT-PCR analysis on the expression levels of the m6A-modified methyltransferases and demethylases demonstrated that only the m6A demethylase fat mass and obesity-associated protein（FTO）was decreased. Using an osteoclast cell model, we confirmed that TLR4-mediated osteoclast differentiation was induced by glycolipid toxicity via inhibition of FTO expression. Taken together, these results suggest that inhibition of TLR4 may prevent diabetic bone loss via regulation of FTO-mediated m6A modification.

Boosting glycolysis to combat fragile bone in type 1 diabetes

Individuals with type 1 diabetes (T1D) have an increased risk of osteoporosis and fracture. In this issue of Cell Chemical Biology, Ji etal.1 show that impaired glucose metabolism in the bone-forming osteoblast drives diabetic osteoporosis in Akita mice, a mouse model of T1D.

AR/PCC herb pair inhibits osteoblast pyroptosis to alleviate diabetes-related osteoporosis by activating Nrf2/Keap1 pathway.

Osteoporosis is a prevalent complication of diabetes, characterized by systemic metabolic impairment of bone mass and microarchitecture, particularly in the spine. Anemarrhenae Rhizoma/Phellodendri Chinensis Cortex (AR/PCC) herb pair has been extensively employed in Traditional Chinese Medicine to manage diabetes; however, its potential to ameliorate diabetic osteoporosis (DOP) has remained obscure. Herein, we explored the protective efficacy of AR/PCC herb pair against DOP using a streptozotocin (STZ)-induced rat diabetic model. Our data showed that AR/PCC could effectively reduce the elevated fasting blood glucose and reverse the osteoporotic phenotype of diabetic rats, resulting in significant improvements in vertebral trabecular area percentage, trabecular thickness and trabecular number, while reducing trabecular separation. Specifically, AR/PCC herb pair improved impaired osteogenesis, nerve ingrowth and angiogenesis. More importantly, it could mitigate the aberrant activation of osteoblast pyroptosis in the vertebral bodies of diabetic rats by reducing increased expressions of Nlrp3, Asc, Caspase1, Gsdmd and IL-1β. Mechanistically, AR/PCC activated antioxidant pathway through the upregulation of the antioxidant response protein Nrf2, while concurrently decreasing its negative feedback regulator Keap1. Collectively, our in vivo findings demonstrate that AR/PCC can inhibit osteoblast pyroptosis and alleviate STZ-induced rat DOP, suggesting its potential as a therapeutic agent for mitigating DOP.

Identification of ferroptosis-related molecular clusters and genes for diabetic osteoporosis based on the machine learning.

Diabetic osteoporosis exhibits heterogeneity at the molecular level. Ferroptosis, a controlled form of cell death brought on by a buildup of lipid peroxidation, contributes to the onset and development of several illnesses. The aim was to explore the molecular subtypes associated with ferroptosis in diabetic osteoporosis at the molecular level and to further elucidate the potential molecular mechanisms. Integrating the CTD, GeneCards, FerrDb databases, and the microarray data of GSE35958, we identified ferroptosis-related genes (FRGs) associated with diabetic osteoporosis. We applied unsupervised cluster analysis to divide the 42 osteoporosis samples from the GSE56814 microarray data into different subclusters based on FRGs. Subsequently, FRGs associated with two ferroptosis subclusters were obtained by combining database genes, module-related genes of WGCNA, and differentially expressed genes (DEGs). Eventually, the key genes from FRGs associated with diabetic osteoporosis were identified using the least absolute shrinkage and selection operator (LASSO), Boruta, support vector machine recursive feature elimination (SVM - RFE), and extreme gradient boosting (XGBoost) machine learning algorithms. Based on ROC curves of external datasets (GSE56815), the model's efficiency was examined. We identified 15 differentially expressed FRGs associated with diabetic osteoporosis. In osteoporosis, two distinct molecular clusters related to ferroptosis were found. The expression results and GSVA analysis indicated that 15 FRGs exhibited significantly different biological functions and pathway activities in the two ferroptosis subclusters. Therefore, we further identified 17 FRGs associated with diabetic osteoporosis between the two subclusters. The results of the comprehensive analysis of 17 FRGs demonstrated that these genes were heterogeneous and had a specific interaction between the two subclusters. Ultimately, the prediction model had a strong foundation and excellent AUC values (0.84 for LASSO, 0.84 for SVM - RFE, 0.82 for Boruta, and 0.81 for XGBoost). IDH1 is a common gene to all four algorithms thus being identified as a key gene with a high AUC value (AUC = 0.698). As a ferroptosis regulator, IDH1 is able to distinguish between distinct molecular subtypes of diabetic osteoporosis, which may offer fresh perspectives on the pathogenesis of the disease's clinical symptoms and prognostic heterogeneity.

The Synergistic Effect of Zuogui Pill and Eldecalcitol on Improving Bone Mass and Osteogenesis in Type 2 Diabetic Osteoporosis.

Background and Objectives: The incidence of diabetic osteoporosis, an important complication of diabetes mellitus, is increasing gradually. This study investigated the combined effect of the Zuogui pill (ZGP) and eldecalcitol (ED-71), a novel vitamin D analog, on type 2 diabetic osteoporosis (T2DOP) and explored their action mechanism. Materials and Methods: Blood glucose levels were routinely monitored in db/db mice while inducing T2DOP. We used hematoxylin and eosin staining, Masson staining, micro-computed tomography, and serum biochemical analysis to evaluate changes in the bone mass and blood calcium and phosphate levels of mice. Immunohistochemical staining was performed to assess the osteoblast and osteoclast statuses. The MC3T3-E1 cell line was cultured in vitro under a high glucose concentration and induced to undergo osteogenic differentiation. Quantitative real-time polymerase chain reaction, Western blot, immunofluorescence, ALP, and alizarin red staining were carried out to detect osteogenic differentiation and PI3K-AKT signaling pathway activity. Results: ZGP and ED-71 led to a dramatic decrease in blood glucose levels and an increase in bone mass in the db/db mice. The effect was strongest when both were used together. ZGP combined with ED-71 promoted osteoblast activity and inhibited osteoclast activity in the trabecular bone region. The in vitro results revealed that ZGP and ED-71 synergistically promoted osteogenic differentiation and activated the PI3K-AKT signaling pathway. The PI3K inhibitor LY294002 or AKT inhibitor ARQ092 altered the synergistic action of both on osteogenic differentiation. Conclusions: The combined use of ZGP and ED-71 reduced blood glucose levels in diabetic mice and promoted osteogenic differentiation through the PI3K-AKT signaling pathway, resulting in improved bone mass. Our study suggests that the abovementioned combination constitutes an effective treatment for T2DOP.

Overexpression of SENP3 promotes PPAR-γ transcription through the increase of HIF-1α stability via SUMO2/3 and participates in molecular mechanisms of osteoporosis

Patients with type II diabetes are exposed to a high risk of osteoporosis. The present study sought to exploit the detailed mechanisms of the SENP3/HIF-1α/PPAR-γ axis in osteoporosis. A rat model of type II diabetic osteoporosis was established, followed by the isolation of bone marrow mononuclear macrophages (BMMs). Gain- and loss-of-function assays were conducted in rat models and BMMs from rat models, followed by the evaluation of SENP3, HIF-1α, and PPAR-γ expression and detection of osteoclast differentiation-related indexes. Next, the SUMOylated modification of HIF-1α and the regulation of SENP3 on SUMOylated modification level of HIF-1α were assessed using immunoprecipitation, and the binding of HIF-1α to the PPARγ promoter was identified with ChIP and dual-luciferase reporter assays. SENP3 and HIF-1α expression was down-regulated in tissues of type II diabetes-induced osteoporotic rats and BMMs, with high SUMOylated modification levels of HIF-1α. Mechanically, HIF-1α was modified by SUMO2/3. SENP3 suppressed SUMOylated modification of HIF-1α and enhanced HIF-1α stability. HIF-1α bound to the PPAR-γ promoter and facilitated PPAR-γ transcription. SENP3 overexpression restrained osteoblast differentiation in type II diabetes-induced osteoporotic rats and BMMs from rat models. SENP3 knockdown facilitated osteoclast differentiation in type II diabetes-induced osteoporotic rats and BMMs from rat models, which was neutralized by further HIF-1α overexpression. To sum up, SENP3 overexpression restrained osteoclast differentiation in type II diabetic osteoporosis by increasing HIF-1α stability and expression and thus promoting PPAR-γ expression via de-SUMOylation, which might expand the understanding of the mechanisms of type II diabetes combined with osteoporosis.

Zoledronate Promotes Peri-Implant Osteogenesis in Diabetic Osteoporosis by the AMPK Pathway.

Together with diabetic osteoporosis (DOP), diabetes patients experience poor peri-implant osteogenesis following implantation for dentition defects. Zoledronate (ZOL) is widely used to treat osteoporosis clinically. To evaluate the mechanism of ZOL for the treatment of DOP, experiments with DOP rats and high glucose-grown MC3T3-E1 cells were used. The DOP rats treated with ZOL and/or ZOL implants underwent a 4-week implant-healing interval, and then microcomputed tomography, biomechanical testing, and immunohistochemical staining were performed to elucidate the mechanism. In addition, MC3T3-E1 cells were maintained in an osteogenic medium with or without ZOL to confirm the mechanism. The cell migration, cellular actin content, and osteogenic differentiation were evaluated by a cell activity assay, a cell migration assay, as well as alkaline phosphatase, alizarin red S, and immunofluorescence staining. The mRNA and protein expression of adenosine monophosphate-activated protein kinase (AMPK), phosphorylated AMPK (p-AMPK), osteoprotegerin (OPG), receptor activator of nuclear factor kappa B ligand (RANKL), bone morphogenetic protein 2 (BMP2), and collagen type I (Col-I) were detected using real-time quantitative PCRs and western blot assays, respectively. In the DOP rats, ZOL markedly improved osteogenesis, enhanced bone strength and increased the expression of AMPK, p-AMPK, and Col-I in peri-implant bones. The in vitro findings showed that ZOL reversed the high glucose-induced inhibition of osteogenesis via the AMPK signaling pathway. In conclusion, the ability of ZOL to promote osteogenesis in DOP by targeting AMPK signaling suggests that therapy with ZOL, particularly simultaneous local and systemic administration, may be a unique approach for future implant repair in diabetes patients.

Physical Therapy Aspects on Diabetic Female Osteoporosis Complication

Abstract Osteoporosis is a disease that affects over 40 percent of women over the age of 50. The diabetes-osteoporosis relationship is complex and still incompletely elucidated, despite numerous studies conducted in recent decades(1). The influence of diabetes on bone tissue differs, however, between the forms of type 1 and type 2 diabetes. The purpose of this paper is to highlight the main aspects of the physical therapy in the prophylaxis and treatment of diabetic osteoporosis in females, in the context of proper guidance and an appropriate exercise program. After 35 years of age, the bone continuously loses its substance, a normal and natural phenomenon with the aging. However, this loss can become a serious problem if the initial "bone reserve" was too low or if the bone loss is done too quickly, and especially after the menopause. The result is an increased risk of fracture, either by a normal fall, like in the wrist or hip, or by a moderate lifting effort, as in the case of the vertebrae. Insufficient physical activity, sedentarism, obesity or low body weight, metabolic disorders with absorption deficits lead to demineralization and bone marrow scarring. So, an appropriate exercise program under the auspices of: resistance, posture, balance, are targets that can activate osteoblast in the process of deposition and collagen construction in the bone matrix. A good exercise program in the prophylaxis and treatment of osteoporosis consists of exercise, posture and balance exercises designed for both upper and lower limbs, but also for abdominal and pelvic belts.

Dipeptidyl peptidase 3 is essential for maintaining osteoblastic differentiation under a high-glucose environment by inhibiting apoptosis, oxidative stress and inflammation through the modulation of the Keap1-Nrf2 pathway

Dipeptidyl peptidase 3 (Dpp3) has emerged as a pivotal mediator of bone homeostasis and bone loss pathology. However, whether Dpp3 plays a role in diabetic osteoporosis has not been addressed. Therefore, this work explored the possible role of Dpp3 in osteoblast dysfunction evoked by high glucose (HG), a cellular model for studying diabetic osteoporosis in vitro. Dpp3 expression was decreased in the pre-osteoblast MC3T3-E1 during osteoblastic differentiation under the HG environment. The osteoblastic differentiation impaired by HG was reversed in Dpp3-overexpressing MC3T3-E1 cells. The migration and invasion of MC3T3-E1 cells impeded by HG were reversed by Dpp3 overexpression. Moreover, HG-evoked apoptosis, oxidative stress and inflammation were ameliorated in Dpp3-overexpressing MC3T3-E1 cells. A mechanistic study showed that Dpp3 up-regulated the activation of nuclear factor E2-related factor 2 (Nrf2) depending on Kelch-like ECH-associated protein 1 (Keap1). The blockade of Nrf2 reversed Dpp3-mediated effects on osteoblastic differentiation, apoptosis, oxidative stress and inflammation of HG-stimulated MC3T3-E1 cells. Therefore, Dpp3 plays an essential role in maintaining osteoblastic differentiation under a HG environment associated with the regulation of the Keap1-Nrf2 pathway. This work indicates a possible relationship between Dpp3 and diabetic osteoporosis.

A static magnetic field improves bone quality and balances the function of bone cells with regulation on iron metabolism and redox status in type 1 diabetes.

Osteoporosis is one of the chronic complications of type 1 diabetes with high risk of fracture. The prevention of diabetic osteoporosis is of particular importance. Static magnetic fields (SMFs) exhibit advantages on improvement of diabetic complications. The biological effects and mechanism of SMFs on bone health of type 1 diabetic mice and functions of bone cells under high glucose have not been clearly clarified. In animal experiment, six-week-old male C57BL/6J mice were induced to type 1 diabetes and exposed to SMF of 0.4-0.7 T for 4 h/day lasting for 6 weeks. Bone mass, biomechanical strength, microarchitecture and metabolism were determined by DXA, three-point bending assay, micro-CT, histochemical and biochemical methods. Exposure to SMF increased BMD and BMC of femur, improved biomechanical strength with higher ultimate stress, stiffness and elastic modulus, and ameliorated the impaired bone microarchitecture in type 1 diabetic mice by decreasing Tb.Pf, Ct.Po and increasing Ct.Th. SMF enhanced bone turnover by increasing the level of markers for bone formation (OCN and Collagen I) as well as bone resorption (CTSK and NFAT2). In cellular experiment, MC3T3-E1 cells or primary osteoblasts and RAW264.7 cells were cultured in 25 mM high glucose-stimulated diabetic marrow microenvironment under differentiation induction and exposed to SMF. SMF promoted osteogenesis with higher ALP level and mineralization deposition in osteoblasts, and it also enhanced osteoclastogenesis with higher TRAP activity and bone resorption in osteoclasts under high glucose condition. Further, SMF increased iron content with higher FTH1 expression and regulated the redox level through activating HO-1/Nrf2 in tibial tissues, and lowered hepatic iron accumulation by BMP6-mediated regulation of hepcidin and lipid peroxidation in mice with type 1 diabetes. Thus, SMF may act as a potential therapy for improving bone health in type 1 diabetes with regulation on iron homeostasis metabolism and redox status.

Non-invasive diagnostic potential of salivary miR-25-3p for periodontal disease and osteoporosis among a cohort of elderly patients with type 2 diabetes mellitus

ObjectiveOsteoporosis (OP) and periodontal disease (PD) are two common health issues that threaten the older population and potentially connected each other in the context of type 2 diabetes mellitus (T2DM). Dysregulated expression of microRNAs (miRNAs) may contribute to the development and progression of both OP and PD among elderly T2DM patients. The present study aimed to evaluate the accuracy of miR-25-3p expression for the detection of OP and PD when compared to a mixed group of patients with T2DM.MethodsThe study recruited 45 T2DM patients with normal bone mineral density (BMD) and healthy periodontium, 40 type 2 diabetic osteoporosis patients coexistent with PD, 50 type 2 diabetic osteoporosis patients with healthy periodontium, and 52 periodontally healthy individuals. miRNA expression measurements in the saliva were determined by real-time PCR.ResultsThe salivary expression of miR-25-3p was higher in type 2 diabetic osteoporosis patients than patients with T2DM only and healthy individuals (P < 0.05). Among type 2 diabetic osteoporosis patients, those with PD exhibited a higher salivary expression of miR-25-3p than those with healthy periodontium (P < 0.05). Among type 2 diabetic patients with healthy periodontium, a higher salivary expression of miR-25-3p was noted in those with OP than those without (P < 0.05). We also found a higher salivary expression of miR-25-3p in T2DM patients than healthy individuals (P < 0.05). It was revealed that the salivary expression of miR-25-3p was increased as the T scores of BMD of patients were lowered, the PPD and CAL values of patients were enhanced. The salivary expression of miR-25-3p used as a test to predict a diagnosis of PD among type 2 diabetic osteoporosis patients, a diagnosis of OP among type 2 diabetic patients, and a diagnosis of T2DM among healthy individuals produced AUC of 0.859. 0.824, and 0.886, respectively.ConclusionThe findings obtained from the study support salivary miR-25-3p confers non-invasive diagnostic potential for PD and OP among a cohort of elderly T2DM patients.

The combination of linagliptin and metformin rescues bone loss in type 2 diabetic osteoporosis

To develop an approach to reduce the type 2 diabetic osteoporosis, this study investigated the protective effects of the combination of linagliptin and metformin against osteoporosis. Micro-CT and dynamic biomechanical measurements were used to determine the bone microstructure in the type 2 diabetes mellitus (T2DM) rats. MC3T3-E1 cells were cultured in high glucose environments. In addition, we used qRT-PCR and Western blotting to assess osteogenic markers and p38 and extracellular signal-regulated kinase (ERK) protein expression. The combination of linagliptin and metformin treatment significantly restored bone micro-architecture and femoral mechanical properties in the T2DM rats. In contrast, bone markers including osteocalcin, NH2-terminal propeptide of type I procollagen, COOH-terminal telopeptide of type I collagen and tartrate-resistant acid phosphatase were significantly reduced by the combination of linagliptin and metformin treatment. We used high glucose treated MC3T3-E1 cells to mimic the condition of T2DM. Linagliptin combined with metformin treatment significantly inhibited the phosphorylation of p38 and ERK induced by high glucose treatment. In conclusion, the linagliptin combined with metformin treatment improved the rats’ bone mineral density, bone structure, and osteogenic markers. Both p38 and ERK phosphorylation were reduced in high glucose MC3T3-E1 cells. Our findings highlight the potential of linagliptin combined with metformin for the treatment of T2DM-related osteoporosis.

THE STATE OF BONE METABOLISM IN PATIENTS WITH GENERALIZED PERIODONTITIS IN DIABETIC OSTEOPATHY

Diagnosis of the state of bone metabolism in patients with generalized periodontitis burdened with type 2 diabetes is an important step in the complex of treatment and prevention measures for this pathology. The purpose of the study was to create evidence-diagnostic criteria for assessing and predicting the severity of the course of generalized periodontitis in diabetic osteopathy based on the study of the variability of bone remodeling. Research material and methods. In order to select homogeneous groups, a clinical and radiological examination of 166 patients with generalized periodontitis, associated and not associated with type 2 diabetes, was conducted. The age of the patients was in the range of 30-50 years (on average 42.5+- 2.34 years). Among them there were 99 (59.6 %) women and 67 (40.4 %) men. The degree of severity of generalized periodontitis was verified according to generally accepted clinical and radiological criteria outlined in modern and domestic classifications: 76 (45.8 %) patients had chronic generalized periodontitis and 90 (54.2 %) had chronic rapidly progressive periodontitis. The control group consisted of 19 almost healthy voluntary donors of similar age (on average 41.5+-2.7 years) and sex without endocrine pathology, with healthy periodontium and intact teeth. Research results and their discussion. Evaluation of the Hounsfield index and markers of bone metabolism in different groups of patients with generalized periodontitis in type 2 diabetes with average statistical analysis showed that they are directly correlated with the severity and the course of generalized periodontitis, the stage of compensation, the severity and duration of diabetes. Conclusions. The peculiarity of the clinical course of generalized periodontitis in type 2 diabetes mellitus, burdened by diabetic osteoporosis, is caused and manifested by a decrease in the bone structures of the periodontium in the processes of osteosynthesis and an increase in the intensity of bone resorption. A feature of the manifestation of rapidly progressive and chronic generalized periodontitis in diabetic osteopathy and without systemic pathology is the increase, independent of the clinical picture of the disease, of signs of osteoporosis activation and a decrease in osteosynthesis. To verify the activity of osteosynthesis and bone resorption in periodontal tissues, the following have predictive value: diagnosis of different directionality and intensity of bone remodeling based on the levels of quantitative content in blood serum of the levels of markers of bone metabolism.

Iron metabolism and ferroptosis in diabetic bone loss: from mechanism to therapy.

Osteoporosis, one of the most serious and common complications of diabetes, has affected the quality of life of a large number of people in recent years. Although there are many studies on the mechanism of diabetic osteoporosis, the information is still limited and there is no consensus. Recently, researchers have proven that osteoporosis induced by diabetes mellitus may be connected to an abnormal iron metabolism and ferroptosis inside cells under high glucose situations. However, there are no comprehensive reviews reported. Understanding these mechanisms has important implications for the development and treatment of diabetic osteoporosis. Therefore, this review elaborates on the changes in bones under high glucose conditions, the consequences of an elevated glucose microenvironment on the associated cells, the impact of high glucose conditions on the iron metabolism of the associated cells, and the signaling pathways of the cells that may contribute to diabetic bone loss in the presence of an abnormal iron metabolism. Lastly, we also elucidate and discuss the therapeutic targets of diabetic bone loss with relevant medications which provides some inspiration for its cure.

D-Pinitol Improved Glucose Metabolism and Inhibited Bone Loss in Mice with Diabetic Osteoporosis.

Diabetic osteoporosis (DO) has been increasingly recognized as an important complication of diabetes. D-pinitol, a natural compound found in various legumes, is known for its anti-diabetic function, but its effect on DO has not been investigated. Two doses of pinitol (50 and 100 mg/kg Bw/d) were administered orally to experimentally induce the DO mouse model for 5 weeks. The results indicated that pinitol suppressed fasting blood glucose levels and tended to enhance impaired pancreatic function. Pinitol also suppressed serum bone turnover biomarkers, and improved dry femur weight, cancellous bone rate, and bone mineral content in the DO mice. Based on the inositol quantification using GC-MS in serum, liver, kidney, and bone marrow, the pinitol treatment significantly recovered the depleted D-chiro-inositol (DCI) content or the decreased the ratio of DCI to myo-inositol caused by DO. In short, our results suggested that pinitol improved glucose metabolism and inhibited bone loss in DO mice via elevating the DCI levels in tissues.

Advanced glycation end products inhibit the osteogenic differentiation potential of adipose-derived stem cells in mice through autophagy

BackgroundDiabetes mellitus (DM) microenvironment will accelerate the accumulation of Advanced glycation end products (AGEs), adipose-derived stem cells (ASCs) have poor osteogenesis in the DM microenvironment. Studies suggest autophagy plays a vital role in osteogenesis, but the mechanism of the altered osteogenic potential of ASCs has not been elucidated. Bone tissue engineering by ASCs is widely used in the treatment of bone defects with diabetic osteoporosis (DOP). Therefore, it is meaningful to explore the effect of AGEs on the osteogenic differentiation potential of ASCs and its potential mechanism for the repair of bone defects in DOP. Materials and methodsASCs in C57BL/6 mice were isolated, cultured, then treated with AGEs, subsequently, cell viability and proliferation were detected through Cell Counting Kit 8 assay. 3-Methyladenine (3-MA), an autophagic inhibitor used to inhibit autophagic levels. Rapamycin (Rapa), an autophagy activator that further activated autophagy levels by inhibiting mTOR.The osteogenesis and autophagy changes of ASCs were analyzed by flow cytometry, qPCR, western blot, immunofluorescence, alkaline phosphatase (ALP) and alizarin red staining. ResultsAGEs reduced the autophagy level and osteogenic potential of ASCs. After 3-MA reduced autophagy, the osteogenic potential of ASCs also decreased. AGEs co-treatment with 3-MA, the levels of osteogenesis and autophagy reduced more significantly. When autophagy was activated by Rapa, it was found that it could rescue the reduced osteogenic potential of AGEs. ConclusionsAGEs reduce the osteogenic differentiation potential of ASCs through autophagy, and may provide a reference for the treatment of bone defects with diabetes osteoporosis.

Glia maturation factor beta deficiency protects against diabetic osteoporosis by suppressing osteoclast hyperactivity

Excessive osteoclast activation, which depends on dramatic changes in actin dynamics, causes osteoporosis (OP). The molecular mechanism of osteoclast activation in OP related to type 1 diabetes (T1D) remains unclear. Glia maturation factor beta (GMFB) is considered a growth and differentiation factor for both glia and neurons. Here, we demonstrated that Gmfb deficiency effectively ameliorated the phenotype of T1D-OP in rats by inhibiting osteoclast hyperactivity. In vitro assays showed that GMFB participated in osteoclast activation rather than proliferation. Gmfb deficiency did not affect osteoclast sealing zone (SZ) formation but effectively decreased the SZ area by decreasing actin depolymerization. When GMFB was overexpressed in Gmfb-deficient osteoclasts, the size of the SZ area was enlarged in a dose-dependent manner. Moreover, decreased actin depolymerization led to a decrease in nuclear G-actin, which activated MKL1/SRF-dependent gene transcription. We found that pro-osteoclastogenic factors (Mmp9 and Mmp14) were downregulated, while anti-osteoclastogenic factors (Cftr and Fhl2) were upregulated in Gmfb KO osteoclasts. A GMFB inhibitor, DS-30, targeting the binding site of GMFB and Arp2/3, was obtained. Biocore analysis revealed a high affinity between DS-30 and GMFB in a dose-dependent manner. As expected, DS-30 strongly suppressed osteoclast hyperactivity in vivo and in vitro. In conclusion, our work identified a new therapeutic strategy for T1D-OP treatment. The discovery of GMFB inhibitors will contribute to translational research on T1D-OP.