Vascular Pericyte-Derived Exosomes Inhibit Bone Resorption via Traf3.

Purpose: Blood vessels distribute cells, oxygen, and nutrients throughout the body to support tissue growth and balance. Pericytes and endothelial cells form the inner wall of blood vessels, crucial for organ development and tissue homeostasis by producing paracrine signaling molecules. In the skeletal system, pericyte-derived vascular factors along with angiogenic factors released by bone cells regulate angiogenesis and bone formation. Although the involvement of angiogenic factors and skeletal blood vessels in bone homeostasis is relatively clear, the role of pericytes and the underlying mechanisms remain unknown. Here, our objective was to elucidate the significance of pericytes in regulating osteoclast differentiation. Methods: We used tissue staining to detect the coverage of pericytes and osteoclasts in femoral tissues of osteoporotic mice and mice of different ages, analyzing their correlation. We developed mice with conditionally deleted pericytes, observing changes in bone mass and osteoclast activity using micro-computer tomography and tissue staining to detect the regulatory effect of pericytes on osteoclasts. Pericytes-derived exosomes (PC-EVs) were collected and co-cultured with monocytes that induce osteoclast differentiation to detect the effect of the former on the exosomes. Finally, the specific mechanism of PC-EVs regulating osteoclast differentiation was verified using RNA sequencing and Western blotting. Results: Our study indicates a significant correlation between pericytes and age-related bone resorption. Conditional deletion of pericytes activated bone resorption and led to osteopenia in vivo. We discovered that PC-EVs inhibited the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway, which is mediated by tumor necrosis factor receptor-associated factor 3 (Traf3), negatively regulating osteoclast development and bone resorption. Silencing Traf3 in PC-EVs canceled their inhibitory effect on osteoclast differentiation. Conclusion: Our study provides a novel perspective into the regulatory role of pericytes on bone resorption and may provide potential strategies for developing novel anti-bone resorption therapies.

Tantalum-incorporated hydroxyapatite coating on titanium implants: its mechanical and in vitro osteogenic properties.

OBJECTIVE: The fabrication of bioactive coatings on metallic implants to enhance osseointegration has become a topic of general interest in orthopedics and dentistry. Hydroxyapatite (HA) coating has been shown to induce bone formation and promote bone-implant integration. Unfortunately, poor mechanical performance has hindered this from becoming a favorable coating material. The majority of present studies have focused in incorporating different elements into HA coatings to improve mechanical properties. In recent years, tantalum (Ta) has received increasing attention due to its excellent biocompatibility and corrosion resistance. The aim of on the present study was to investigate the fabrication and biological performance of Ta-incorporated HA coatings. METHODS: Ta-incorporated HA coatings were fabricated using the plasma spray technique on a titanium substrate, and the surface characteristics and mechanical properties were examined. In addition, the effects of Ta-incorporated HA coatings on the biological behavior of mesenchymal stem cells (BMSCs) were investigated. RESULTS: Ta-incorporated HA coatings with microporous structure had higher roughness and wettability. In addition, the bonding strength of Ta/HA coatings with the substrate was substantially superior to HA coatings. Furthermore, Ta-incorporated HA coatings not only facilitated initial cell adhesion and faster proliferation, but also promoted the osteogenic differentiation of BMSCs. CONCLUSION: These results indicate that the incorporation of Ta could improve mechanical performance and increase the osteogenic activity of HA coatings. The Ta-incorporated HA coating fabricated by plasma spraying is expected to be a promising bio-coating material for metallic implants.

Poor Sleep Quality Is Associated with a Higher Risk of Pulmonary tuberculosis in Patients with a Type 2 Diabetes Mellitus Course for More than 5 Years.

A case-control study was conducted in Shandong from January to December 2017 to explore the relationship between sleep quality and the risk of active pulmonary tuberculosis (PTB). Seventy-nine patients with type 2 diabetes mellitus coincident with newly diagnosed pulmonary tuberculosis (DM-PTB) and 169 age, sex, and DM course frequency-matched controls (DM alone) were enrolled. Univariate and multivariable unconditional logistic regression analyses were conducted. We further conducted subgroup analyses to explore the relationship between sleep quality and PTB risk, including DM course (≤5 and ＞5 years), age, sex, and the presence of overweight or obesity (body mass index (BMI) ＞ 24 kg/m2). Multivariate logistic regression demonstrated that poor sleep quality had a borderline negative association with the odds of PTB (P ＝ 0.065). Subgroup multivariate analyses showed that poor sleep quality increased the risk of PTB to more than 3 times among patients with a DM course ＞ 5 years (odds ratio 3.31, 95% confidence interval: 1.08-10.13; P ＝ 0.036) after adjusting for potential confounding factors including residential area, educational level, BMI, history of contact with tuberculosis patients, smoking, alcohol consumption, physical exercise, immune status, and frequency of blood glucose monitoring. In conclusion, poor sleep quality is an independent risk factor of PTB among DM patients with a course of ＞ 5 years, which indicates significant epidemiological implications for PTB control.

Enhanced bone regeneration using an insulin-loaded nano-hydroxyapatite/collagen/PLGA composite scaffold.

Insulin is widely considered as a classical hormone and drug in maintaining energy and glucose homeostasis. Recently, insulin has been increasingly recognized as an indispensable factor for osteogenesis and bone turnover, but its applications in bone regeneration have been restricted because of the short periods of activity and uncontrolled release. In this study, we incorporated insulin-loaded poly lactic-co-glycolic-acid (PLGA) nanospheres into nano-hydroxyapatite/collagen (nHAC) scaffolds and investigated the bioactivity of the composite scaffolds in vitro and in vivo. Bioactive insulin was successfully released from the nanospheres within the scaffold, and the release kinetics of insulin could be efficiently controlled by uniform-sized nanospheres. The physical characterizations of the composite scaffolds demonstrated that incorporation of nanospheres in nHAC scaffolds using this method did not significantly change the porosity, pore diameters, and compressive strengths of nHAC. In vitro, the insulin-loaded nHAC/PLGA composite scaffolds possessed favorable biological function for bone marrow mesenchymal stem cells adhesion and proliferation, as well as the differentiation into osteoblasts. In vivo, the optimized bone regenerative capability of this composite scaffold was confirmed in rabbit mandible critical size defects. These results demonstrated successful development of a functional insulin-PLGA-nHAC composite scaffold that enhances the bone regeneration capability of nHAC.

Osseointegration of layer-by-layer polyelectrolyte multilayers loaded with IGF1 and coated on titanium implant under osteoporotic condition.

PURPOSE: Titanium implant is a widely used method for dental prosthesis restoration. Nevertheless, in patients with systemic diseases, including osteoporosis, diabetes, and cancer, the success rate of the implant is greatly reduced. This study investigates a new implant material loaded with insulin-like growth factor 1 (IGF1), which could potentially improve the implant success rate, accelerate the occurrence of osseointegration, and provide a new strategy for implant treatment in osteoporotic patients. MATERIALS AND METHODS: Biofunctionalized polyelectrolyte multilayers (PEMs) with polyethylenimine as the excitation layer and gelatin/chitosan loaded with IGF1 were prepared on the surface of titanium implant by layer-by-layer self-assembly technique. The physical and chemical properties of the biofunctionalized PEMs, the biological characteristics of bone marrow mesenchymal stem cells (BMMSCs), and bone implant contact correlation test indexes were detected and analyzed in vitro and in vivo using osteoporosis rat model. RESULTS: PEMs coatings loaded with IGF1 (TNS-PEM-IGF1-100) implant promoted the early stage of BMMSCs adhesion. Under the action of body fluids, the active coating showed sustained release of growth factors, which in turn promoted the proliferation and differentiation of BMMSCs and the extracellular matrix. At 8 weeks from implant surgery, the new bone around the implants was examined using micro-CT and acid fuchsin/methylene blue staining. The new bone formation increased with time in each group, while the TNS-PEM-IGF1-100 group showed the highest thickness and continuity. CONCLUSION: TNS-PEM-IGF1-100 new implants can promote osseointegration in osteoporotic conditions both in vivo and in vitro and provide a new strategy for implant repair in osteoporotic patients.

Site-Specific Characteristics of Bone Marrow Mesenchymal Stromal Cells Modify the Effect of Aging on the Skeleton.

Bone is a self-renewing tissue. Bone marrow mesenchymal stromal cells (BMSCs) are located in the adult skeleton and are believed to be involved in the maintenance of skeletal homeostasis throughout life. With increasing age, the ability of the skeleton to repair itself decreases, possibly due to the reduced functional capacity of BMSCs. Recent evidence has suggested the existence of at least two populations of BMSCs with different embryonic origins that cannot be interchanged during stem cell recruitment: craniofacial BMSCs (neural crest origin) and appendicular BMSCs (mesoderm origin). Questions arise as to whether the site-specific characteristics alter the effect of aging on the skeleton. In this study, the effects of biological aging on human BMSCs were compared with BMSCs derived from the craniofacial bone versus those derived from the appendicular skeleton. The phenotype, proliferation, and functional characteristics (osteogenic differentiation, cytokine secretion, and bone formation in vivo) of the BMSCs were investigated. The results demonstrated that the proliferative capacity and osteogenic differentiation of the BMSCs decrease significantly with age both in vitro and in vivo. For age-matched groups, the osteogenic differentiation capacity of alveolar BMSCs was higher than that of femoral BMSCs in the middle-aged and old groups, while there was no significant difference for the young groups. Compared with old alveolar BMSCs, old femoral BMSCs had a significantly longer population doubling time, a smaller colony-forming population, and less bone formation in vivo, while there was no significant difference for the young and middle-aged groups. Distinct differences in the expression of cytokine factors were also found. In conclusion, human BMSCs display an age-related decrease in functional capacity, and embryonic origins may play a critical role in mediating the aging rate of BMSCs. These data provide novel insights into the skeletal site-specific characteristics of aged BMSCs.

Relationship between Type 2 Diabetes and Inflammation Diseases: Cohort Study in Chinese Adults.

BACKGROUND: This study aimed to investigate the association of seven common inflammatory diseases with Type 2 diabetes (T2D) in the Chinese Mainland population. METHODS: Participants were recruited from a great swathe of mainland from 2009 to 2013 for the cohort study. The demographic characteristics between patients with T2D or with inflammatory diseases, including age, sex, smoking status, hypertension etc. were analyzed using the χ(2) test. Cox proportional hazard regression models were used to determine the independent effects of diabetes on the risks of any types of inflammatory diseases in the model and age, sex, hypertension and gout adjusted were used after that. RESULTS: A total of 39367 participants were enrolled in the study and 1634 (4.2%) subjects with missing information on T2D and the inflammatory diseases were excluded. Compared to those without diabetes, after adjusting for age, sex, hypertension and gout, the incidences of asthma, chronic hepatitis, chronic bronchitis, chronic gastroenteritis, chronic gastritis or ulcer in diabetic patients were independently higher, with odd ratios of 0.235 (95% Confidence Interval [CI], 0.117-0.473), 0.845 (95% CI, 0.731-0.976), 0.585 (95% CI, 0.540-0.634), 0.875 (95% CI, 0.806-0.951), 0.843 (95% CI, 0.787-0.903) respectively. Only inflammatory hemorrhoid did not show any clinical significance. CONCLUSION: There was a decreased incidence of inflammatory diseases in the diabetic patients compared with non-diabetic subjects. Except for inflammatory hemorrhoid, asthma, chronic hepatitis, chronic bronchitis, chronic gastroenteritis, chronic gastritis and ulcer were associated with T2D of Chinese individuals, independently of hypertension and gout, and T2D might reduce the risk of these diseases.