Reactive oxygen species-responsive supramolecular deucravacitinib self-assembly polymer micelles alleviate psoriatic skin inflammation by reducing mitochondrial oxidative stress.

Introduction: The new topical formula is urgent needed to meet clinical needs for majority mild patients with psoriasis. Deucravacitinib exerts outstanding anti-psoriatic capacity as an oral TYK2 inhibitor; however, single therapy is insufficient to target the complicated psoriatic skin, including excessive reactive oxygen species (ROS) and persistent inflammation. To address this need, engineered smart nano-therapeutics hold potential for the topical delivery of deucravacitinib. Methods: hydrophobic Deucravacitinib was loaded into polyethylene glycol block-polypropylene sulphide (PEG-b-PPS) for transdermal delivery in the treatment of psoriasis. The oxidative stress model of HaCaT psoriasis was established by TNF-α and IL-17A in vitro. JC-1 assay, DCFH-DA staining and mtDNA copy number were utilized to assess mitochondrial function. 0.75% Carbopol®934 was incorporated into SPMs to produce hydrogels and Rhb was labeled to monitor penetration by Immunofluorescence. In vivo, we established IMQ-induced psoriatic model to evaluate therapeutic effect of Car@Deu@PEPS. Results: Deu@PEPS exerted anti-psoriatic effects by restoring mitochondrial DNA copy number and mitochondrial membrane potential in HaCaT. In vivo, Car@Deu@PEPS supramolecular micelle hydrogels had longer retention time in the dermis in the IMQ-induced ROS microenvironment. Topical application of Car@Deu@PEPS significantly restored the normal epidermal architecture of psoriatic skin with abrogation of splenomegaly in the IMQ-induced psoriatic dermatitis model. Car@Deu@PEPS inhibited STAT3 signaling cascade with a corresponding decrease in the levels of the differentiation and proliferative markers Keratin 17 and Cyclin D1, respectively. Meanwhile, Car@Deu@PEPS alleviated IMQ-induced ROS generation and subsequent NLRP3 inflammasome-mediated pyroptosis. Conclusion: Deu@PEPS exerts prominent anti-inflammatory and anti-oxidative effects, which may offers a more patient-acceptable therapy with fewer adverse effects compared with oral deucravacitinib.

Wnt5a deficiency in osteocalcin-expressing cells could not alleviate the osteoarthritic phenotype in a mouse model of post-traumatic osteoarthritis.

Objectives: Wnt5a, which regulates the activities of osteoblasts and osteoclasts, is reportedly overexpressed in osteoarthritis (OA) tissues. The purpose of this study was to elucidate its role in the development of OA by deleting Wnt5a in osteocalcin (OCN)-expressing cells. Materials and Methods: Knee OA was induced by anterior cruciate ligament transection (ACLT) in OCN-Cre;Wnt5afl/fl knockout (Wnt5a-cKO) mice and control littermates. Eight weeks after surgery, histological changes, cell apoptosis, and matrix metabolism of cartilage were evaluated by toluidine blue, TUNEL staining, and im-immunohistochemistry analyses, respectively. In addition, the subchondral bone microarchitecture of mice was examined by micro-computed tomography (micro-CT). Results: Histological scores show substantial cartilage degeneration occurred in ACLT knees, coupled with decreased collagen type II expression and enhanced matrix metalloproteinase 13 expression, as well as higher proportions of apoptotic cells. Micro-CT results show that ACLT resulted in decreased bone mineral density, bone volume/trabecular volume, trabecular number, and structure model index of subchondral bones in both Wnt5a-cKO and control littermates; although Wnt5a-cKO mice display lower BMD and BV/TV values, no significant difference was observed between Wnt5a-cKO and control mice for any of these values. Conclusion: Our findings indicate that Wnt5a deficiency in OCN-expressing cells could not prevent an osteoarthritic phenotype in a mouse model of post-traumatic OA.

Expression of lncRNA LINC00943 in lung squamous cell carcinoma and its relationship with tumor progression.

BACKGROUND: Molecular biology has been applied to the diagnosis, prognosis and treatment of various diseases, and long noncoding RNA LINC00943 (lncRNA LINC00943; LINC00943) plays an important role in a variety of cancers. Therefore, this study explored the prognostic role of LINC00943 in lung squamous cell carcinoma (LUSC) and understood its impact on the development of LUSC. METHODS: There are 89 LUSC patients were involved in current assay. By detecting the expression of LINC00943 and miR-196b-5p in tissues and cells, LINC00943 and its correlation with the characteristics of clinical data were analyzed. The biological function of LINC00943 was studied by Transwell migration and invasion assays. In addition, Pearson correlation coefficient and luciferase activity experiments were chosen to characterize the relationship between LINC00943 and miR-196b-5p and explore the mechanism of LINC00943. RESULTS: Compared with normal controls, LINC00943 expression in LUSC tissues and cells was significantly reduced, miR-196b-5p was markedly increased, there was a negative correlation between LINC00943 and miR-196b-5p. According to the in vitro cell experiments, migration and invasion of LUSC cells were suppressed by overexpression of LINC00943. Besides, LINC00943 was demonstrated to have prognostic power and targeting miR-196b-5p was involved in the progression of LUSC. CONCLUSIONS: Overexpression of LINC00943 was molecular sponge for miR-196b-5p that controlled the deterioration of LUSC, which had great potential as a prognostic biomarker for LUSC.

Effects of alendronate on cartilage lesions and micro-architecture deterioration of subchondral bone in patellofemoral osteoarthritic ovariectomized rats with patella-baja.

BACKGROUND: Patellofemoral osteoarthritis (PFJOA) is a subtype of knee OA, which is one of the main causes of anterior knee pain. The current study found an increased prevalence of OA in postmenopausal women, called postmenopausal OA. Therefore, we designed the ovariectomized rat model of patella baja-induced PFJOA. Alendronate (ALN) inhibits osteoclast-mediated bone loss, and has been reported the favorable result of a potential intervention option of OA treatment. However, the potential effects of ALN treatment on PFJOA in the ovariectomized rat model are unknown and need further investigation prior to exploration in the clinical research setting. In this study, the effects of ALN on articular cartilage degradation and subchondral bone microstructure were assessed in the ovariectomized PFJOA rat model for 10 weeks. METHODS: Patella baja and estrogen withdrawal were induced by patellar ligament shortening (PLS) and bilateral ovariectmomy surgeries in 3-month-old female Sprague-Dawley rats, respectively. Rats were randomly divided into five groups (n = 8): Sham + V; OVX + V, Sham + PLS + V, OVX + PLS + V, OVX + PLS + ALN (ALN: 70 µg/kg/week). Radiography was performed to evaluate patellar height ratios, and the progression of PFJOA was assessed by macroscopic and microscopic analyses, immunohistochemistry and micro-computed tomography (micro-CT). RESULTS: Our results found that the patella baja model prepared by PLS can successfully cause degeneration of articular cartilage and subchondral bone, resulting in changes of PFJOA. OVX caused a decrease in estrogen levels in rats, which aggravated the joint degeneration caused by PFJOA. Early application of ALN can delay the degenerative changes of articular cartilage and subchondral bone microstructure in castrated PFJOA rat to a certain extent, improve and maintain the micrometabolism and structural changes of cartilage and subchondral bone. CONCLUSION: The early application of ALN can delay the destruction of articular cartilage and subchondral bone microstructure in castrated PFJOA rat to a certain extent.

[Effects of fine particulate matter on bone mass and osteogenic differentiation of bone marrow mesenchymal stem cells in mice].

OBJECTIVE: To observe the effects of exposure to fine particulate matter(PM_(2.5)) on bone mass, microstructure, biomechanical properties, and osteogenic differentiation ability of bone marrow mesenchymal stem cells(BMSCs) in mice. METHODS: A total of 16 C57BL/6J mice aged 8 weeks were randomly divided into control group(NS group) and PM_(2.5) exposure group(PM group). NS group was given normal saline, PM group was given 14 mg/kg PM_(2.5) suspension, 50 µL, poisoning every 3 day. After 10 weeks, the lungs of mice were taken for HE staining, and the left tibia was taken for Micro CT detection to analyze parameters related to cancellous and cortical bone. The right tibia was taken for HE staining to observe changes in bone trabeculae. Immunohistochemical staining was used to detect type I collagen(Col I), osteoprotegerin(OPG), and nuclear factor-κB receptor activating factor ligand(RANKL) protein expression, tartrate resistant acid phosphatase(TRAP) staining for detection of osteoclasts. Extract primary BMSCs from bilateral femurs, induce osteogenesis, and then perform alkaline phosphatase(ALP) staining to detect ALP activity, alizarin red staining to detect bone mineralization ability, real-time PCR to detect osteocalcin(OCN), ALP, OPG, and RANKL mRNA expression, and biomechanical testing to test the mechanical properties of the femur. RESULTS: Compared with the NS group, the pulmonary alveolar structure of the PM group mice was disrupted and a large number of inflammatory cells gathered. Prompt for successful PM_(2.5) poisoning operation. Micro CT result showed that the bone mineral density(BMD) and bone volume fraction(BV/TV) of the PM group mice were 276.959±15.152 mg/cm~3 and 0.208%±0.009%, respectively. The NS group had 316.709±28.205 mg/cm~3 and 0.236%±0.019%, respectively. The PM group was lower than the NS group(P<0.05), but the trabecular number(Tb. N) There was no statistically significant difference in parameters such as trabecular thickness(Tb. Th) and trabecular separation(Tb. SP)(P>0.05). The HE staining result of the tibia showed that the trabeculae in the NS group were thick, dense, and uniform. The bone trabeculae in the PM group were slender, with a decrease in number, widened spacing, and sparse arrangement. The expression of Col I(0.023±0.009) and OPG(0.036±0.010) in the PM group increased compared to the NS group(0.079±0.007, 0.059±0.012), while the expression of RANKL(0.036±0.006) decreased compared to the NS group(0.022±0.002)(P<0.05); The number of TRAP positive particles increased in the PM group. The experimental result after osteoinduction of BMSCs in mice showed that compared with the NS group, the PM group had a decrease in the number of ALP positive cells and a decrease in the number of calcium nodules. The relative expression of ALP, OCN, and OPG mRNA in the PM group(0.375±0.021, 0.585±0.088, 0.768±0.112) was significantly reduced compared to the NS group(1.001±0.043, 1.006±0.132, 1.002±0.086), while the relative expression of RANKL mRNA(1.278±0.118) was increased compared to the NS group(1.001±0.057)(P<0.05). The biomechanical experimental result showed that the maximum deflection of the NS group was 0.337±0.031 mm, while the maximum deflection of the PM group was 0.258±0.041 mm. Compared with the NS group, the maximum deflection of the PM group decreased significantly(P<0.05), and the maximum stress and maximum load showed a decreasing trend, but the difference was not statistically significant(P>0.05). CONCLUSION: After 10 weeks of exposure to PM_(2.5), it can affect the bone health of mice, and its mechanism may be related to increased osteoclast activity and inhibition of the osteogenic differentiation ability of BMSCs.

Strontium ranelate retards disc degradation and improves endplate and bone micro-architecture in ovariectomized rats with lumbar fusion induced - Adjacent segment disc degeneration.

Objectives: Adjacent segment disc degeneration (ASDD) is one of the long-term sequelae of spinal fusion, which is more susceptible with osteoporosis. As an anti-osteoporosis drug, strontium ranelate (SR) has been reported to not only regulate bone metabolism but also cartilage matrix formation. However, it is not yet clear whether SR has a reversal or delaying effect on fusion-induced ASDD in a model of osteoporosis. Materials and methods: Fifth three-month-old female Sprague-Dawley rats that underwent L4-L5 posterolateral lumbar fusion (PLF) with spinous-process wire fixation 4 weeks after bilateral ovariectomy (OVX) surgery. Animals were administered vehicle (V) or SR (900 mg/kg/d) orally for 12 weeks post-PLF as follows: Sham+V, OVX + V, PLF + V, OVX + PLF + V, and OVX + PLF + SR. Manual palpation and X-ray were used to evaluate the state of lumbar fusion. Adjacent-segment disc was assessed by histological (VG staining and Scoring), histomorphometry (Disc Height, MVD, Calcification rate and Vascular Bud rate), immunohistochemical (Col-II, Aggrecan, MMP-13, ADAMTS-4 and Caspase-3), and mRNA analysis (Col-I, Col-II, Aggrecan, MMP-13 and ADAMTS-4). Adjacent L6 vertebrae microstructures were evaluated by microcomputed tomography. Results: Manual palpation and radiographs showed clear evidence of the fused segment's immobility. After 12 weeks of PLF surgery, a fusion-induced ASDD model was established. Low bone mass caused by ovariectomy can significantly exacerbate ASDD progression. SR exerted a protective effect on adjacent segment intervertebral disc with the underlying mechanism possibly being associated with preserving bone mass to prevent spinal instability, maintaining the functional integrity of endplate vascular microstructure, and regulating matrix metabolism in the nucleus pulposus and annulus fibrosus. Discussion: Anti-osteoporosis medication SR treatments not only maintain bone mass and prevent fractures, but early intervention could also potentially delay degenerative conditions linked to osteoporosis. Taken together, our results suggested that SR might be a promising approach for the intervention of fusion-induced ASDD with osteoporosis.

Effect of 10-year cumulative blood pressure exposure on atherosclerotic cardiovascular disease of different age groups: kailuan cohort study.

Background: The level at which cumulative blood pressure (BP) can increase the risk of ASCVD in different age groups remains unclear. This study aimed to investigate the association of 10-year cumulative BP levels with the long-term risk of ASCVD of different age groups. Methods: Cumulative BP exposure was assessed using the time-weighted average (TWA) BP divided into four BP groups. The participants were also divided into four groups according to their baseline age (<50, 50-59, 60-69, or ≥70 years). The association between TWA BP and the risk of ASCVD was assessed by age group using multivariate Cox models. The China-PAR prediction model was used to assess the ability of TWA BP to predict ASCVD. Results: In the group aged <50 years, the hazard ratios and 95% confidence intervals for the risk of ASCVD were 2.66 (1.04-6.80), 3.38 (1.54-7.43), and 3.13 (1.36-7.24) for the elevated BP, stage 1 hypertension, and stage 2 hypertension groups, respectively, when compared with the normal BP group. There was a significant difference in the risk of ASCVD between the age groups, with participants aged <50 years having the highest risk, followed by those aged 50-59, 60-69, and ≥70 years. Conclusions: The risk of ASCVD with high cumulative BP exposure was age-dependent, with a gradual decrease in risk with increasing age.

Association of life's essential 8 and risk of fragility fractures: A large cohort study.

Cardiovascular health (CVH) score is not only associated with cardiovascular diseases, but also some disorders in other systems. This study aims to investigate the association between CVH score and the risk of fragility fractures. The analysis enrolled 89,464 participants at baseline in Kailuan study initiated in 2006-2007. All participants were then followed up every 2 years and the incidence of fragility fractures was recorded annually. A total CVH score was classified as low (0-49 points), moderate (50-79 points), and ideal (80-100 points). The primary outcome was incident fragility fractures before December 31, 2021. Kaplan-Meier was used to estimate cumulative incidence. Multivariable adjusted Cox proportional hazards regression models and time-dependent Cox hazards regression models were used to estimate fragility fracture hazard ratios (aHR) and 95% confidence intervals (95% CI). After 13.98 ± 2.84 years of follow-up, a total of 1534 cases of fragility fractures were identified, with an incidence density of 1.23 per 1000 person-years. Compared with the low CVH group, the risk of fragility fractures was significantly lower in moderate (aHR = 0.78, 95% CI: 0.66-0.92) and ideal CVH groups (aHR = 0.65, 95% CI: 0.51-0.83), particularly in the age <60 group (aHR = 0.72, 95% CI: 0.59-0.88; aHR= 0.55, 95% CI: 0.41-0.73, respectively). Time-dependent Cox hazards regression models, sensitivity analysis, and death competition model confirmed the reliability of these findings. The ideal CVH score is associated with a decreased risk of fragility fractures. With the increase of CVH score, the risk of fragility fracture decreases.

Arterial stiffness and risk of new-onset fragility fracture in Chinese men and women: The Kailuan cohort study.

BACKGROUND: Previous studies have shown an association between increased arterial stiffness and reduced bone mineral density. However, the relationship between arterial stiffness and fragility fracture remains unclear. In this study, we explored the impact of arterial stiffness on the risk of new-onset fragility fracture. METHODS: The study included 53,107 participants in the Kailuan Study in whom brachial-ankle pulse wave velocity (baPWV) measurements were obtained between 2010 and 2021. All participants were free of fragility fractures at baseline. A Cox proportional hazard regression model was used to estimate the hazard ratio (HR) and 95 % confidence interval (CI) for incident fragility fracture on the baseline baPWV groups: <1400 cm/s (reference), 1400 ≤ baPWV < 1800 cm/s, and ≥1800 cm/s. RESULTS: In total, 327 incident fragility fractures were recorded during an average follow-up of 4.99 ± 3.02 years. After adjustment for potential confounders, the HR for the risk of new-onset fragility fracture was 1.66 (95 % CI 1.14-2.42) for the arterial stiffness group in comparison with the normal baPWV group. The risk of fragility fracture was higher in men (HR 1.64, 95 % CI 1.05-2.57). There was a linear association between higher baPWV and fragility fracture. CONCLUSIONS: Arterial stiffness as measured by baPWV was associated with the risk of fragility fracture.

Cumulative exposure to remnant cholesterol and the risk of fragility fractures: a longitudinal cohort study.

Objective: To investigate the association between cumulative remnant cholesterol (cumRC) and the risk of new-onset fragility fractures. Methods: This study included individuals who participated in the 2006, 2008, and 2010 Kailuan health examinations. Baseline characteristics were compared between groups according to cumRC quartiles. The incidence density was calculated, and the log-rank test was used to compare the cumulative incidence. Cox proportional hazards models were used to estimate the hazard ratio (HR) and 95% confidence interval (CI), and restricted cubic spline was used to examine the possibly non-linear relation between cumRC and the risk of fragility fractures. Additional analyses were performed with stratification by age (≥ or <65 years). Results: A total of 43,839 individuals were included in this study. During the median follow-up period of 10.97 years, a total of 489 fragility fractures occurred. Multivariable Cox proportional hazards regression model 3 showed that the Q1 and Q4 groups versus the Q2 group were associated with a higher HR of fragility fracture (HR 1.61, 95% CI: 1.23-2.11; HR 1.38, 95% CI: 1.06-1.81), and restricted cubic spline regression analysis showed a non-linear relationship between cumRC level and the risk of fragility fractures (P Overall association < 0.001, P Non-linear association = 0.001). The association was significant in the age group <65 years but not in the age group ≥65 years. The sensitivity analyses were consistent with the main results. Conclusions: Both too high and too low cumRC levels were associated with a greater risk of fragility fractures, and this association was more significant in young and middle-aged people.

Estrogen deficiency impedes fracture healing despite eliminating the excessive absorption of the posterior callus in a semi-fixed distal tibial fracture mouse model.

BACKGROUND: Treatment of distal tibial fractures is a challenge due to their specific anatomical location. However, there is no appropriate mouse model to simulate a clinical distal tibial fracture for basic research. The aim of this investigation was to evaluate the feasibility of simulating a clinical fracture of the distal tibia of mice and to investigate the effect of ovariectomy (OVX)-induced osteoporosis on fracture healing in this model. METHODS: Sixty female 8-week-old C57BL/6 mice were randomly divided into two groups, either sham or OVX. A semi-fixation distal tibia fracture was established in the right tibia after 8 weeks of OVX. The right tibias were collected at 7, 14, 21, and 28 days post fracture. RESULTS: In the semi-fixation distal tibia fracture model, the posterior callus in the sham group showed excessive bone resorption and lower bone mass phenotype compared with the anterior site; a similar trend was not found in the OVX group. At 28 days post fracture, the posterior callus was more mineralized than the anterior callus in the OVX group. Although the fracture healing of the sham group showed a special phenotype in this mode, the progress and quality of fracture healing were still better than those of the OVX group. CONCLUSION: A semi-fixed distal tibial closed fracture mouse model was successfully established. In this model, excess bone resorption of the posterior callus impaired normal fracture healing, but not in OVX-induced osteoporotic bone. Although the stress shielding effect was not observed in the OVX group, impaired bone healing caused by OVX was still present. Our results suggest that this fracture model may have potential for studies on distal tibial fractures and stress shielding.

Impacts and mechanisms of PM2.5 on bone.

Osteoporosis is a metabolic bone disease, which is characterized by a decreased bone mass and deterioration of bone microstructure, resulting in increased bone fragility and a higher risk of fracture. The main pathological process of osteoporosis is the dynamic imbalance between bone absorption and bone formation, which can be caused by various factors such as air pollution. Particulate matter (PM)2.5 refers to the fine particles in the atmosphere, which are small in volume and large in specific surface area. These particles are prone to carrying toxic substances and have negative effects on several extrapulmonary organs, including bones. In this review, we present relevant data from studies, which show that PM2.5 is associated with abnormal bone turnover and osteoporosis. PM2.5 may cause or aggravate bone loss by stimulating an inflammatory response, inducing oxidative damage, reducing estrogen efficiency by competitive binding to estrogen receptors, or endocrine disorder mediated by binding with aromatic hydrocarbon receptors, and affecting the synthesis of vitamin D to reduce calcium absorption. The cellular and molecular mechanisms involved in these processes are also summarized in this review.

Liraglutide in Combination with Insulin Has a Superior Therapeutic Effect to Either Alone on Fracture Healing in Diabetic Rats.

Purpose: Fractures in patients with type 2 diabetes mellitus are at a high risk of delayed union or non-union. Previous studies have shown a protective effect of liraglutide on bone. In the present study, we aimed to investigate the effects of a combination of liraglutide and insulin on fracture healing in a rat model of diabetes and the mechanisms involved. Materials and Methods: Closed femoral mid-shaft fractures were established in male Sprague-Dawley rats with or without diabetes mellitus, and the diabetic rats were administered insulin and/or liraglutide. Six weeks after femoral fracture, the femoral callus was evaluated by immunohistochemistry, histology, and micro-computed tomography. Additionally, the effects of liraglutide on high-glucose-stimulated MC3T3-E1 cells were analyzed by Western blotting. Results: Micro-computed tomography and safranin O/fast green staining showed that fracture healing was delayed in the diabetic rats, and this was accompanied by much lower expression of osteogenic markers and greater osteoclast activity. However, treatment with insulin and/or liraglutide prevented these changes. Liraglutide in combination with insulin treatment resulted in lower blood glucose concentrations and significantly higher osteocalcin (OCN) and collagen I (Col I) expression six weeks following fracture. Western blot analysis showed that liraglutide prevented the low expression of the bone morphogenetic protein-2, osterix/SP7, OCN, Col I, and ß-catenin in high-glucose-stimulated MC3T3-E1 cells. Conclusion: These results demonstrate that insulin and/or liraglutide promotes bone fracture healing in the DF model. The combination was more effective than either single treatment, which may be because of the two drugs' additive effects on the osteogenic ability of osteoblast precursors.

New-onset stroke on the risk of hip fracture: the Kailuan cohort study in China.

PURPOSE: Stroke is a documented risk factor for hip fracture(HF). However, no data is currently available on this issue in mainland China, we therefore assessed the risk of hip fracture after new-onset stroke using a cohort study. METHODS: This study included 165,670 participants without a history of stroke at baseline from the Kailuan study. All participants were followed biennially until December 31, 2021. During follow-up, a total of 8,496 new-onset stroke cases were identified. For each case subject, four control subjects was randomly selected, matched for age (± 1 years) and sex. The final analysis comprised 42,455 pair-matched cases and controls. A multivariate Cox proportional hazard regression model was used to estimate the effect of new-onset stroke on the risk of hip fracture. RESULTS: During an average follow-up of 8.87 (3.94) years, a total of 231 hip fracture cases occurred, 78 cases in the stroke group and 153 cases in the control group, with incidence rates of 1.12 and 0.50 per 1000 person-years, respectively. The cumulative incidence of the stroke group was higher than that of the controls (P < 0.01). The adjusted hazard ratio (95% confidence interval) of hip fractures in the stroke group was 2.35 (1.77 to 3.12) (P < 0.001) to controls. After stratifying by gender, age, and body mass index, the higher risk was revealed in female (HR 3.10, 95 CI: 2.18 to 6.14, P < 0.001), age < 60 years old (HR 4.12, 95% CI: 2.18 to 7.78, P < 0.001), and non-obesity (BMI<28 kg/m2) (HR 1.74, 95% CI:1.31 to 2.31, P < 0.001) subgroup. CONCLUSIONS: Stroke significantly increases the risk of hip fracture, strategy for protecting stroke patients from falls and hip fractures should be emphasized in poststroke long-term management, particularly the female, age < 60 years old, and non-obese patients.

The role of wnt signaling in diabetes-induced osteoporosis.

Osteoporosis, a chronic complication of diabetes mellitus, is characterized by a reduction in bone mass, destruction of bone microarchitecture, decreased bone strength, and increased bone fragility. Because of its insidious onset, osteoporosis renders patients highly susceptible to pathological fractures, leading to increased disability and mortality rates. However, the specific pathogenesis of osteoporosis induced by chronic hyperglycemia has not yet been fully elucidated. But it is currently known that the disruption of Wnt signaling triggered by chronic hyperglycemia is involved in the pathogenesis of diabetic osteoporosis. There are two main types of Wnt signaling pathways, the canonical Wnt signaling pathway (ß-catenin-dependent) and the non-canonical Wnt signaling pathway (non-ß-catenin-dependent), both of which play an important role in regulating the balance between bone formation and bone resorption. Therefore, this review systematically describes the effects of abnormal Wnt pathway signaling on bone homeostasis under hyperglycemia, hoping to reveal the relationship between Wnt signaling and diabetic osteoporosis to further improve understanding of this disease.

Pulse Pressure Variability and the Risk of Fragility Fracture: The Kailuan Prospective Cohort Study in China.

OBJECTIVES: To investigate the association of the magnitude and direction of pulse pressure variability (PPV) with the incidence of fragility fracture in the general population. METHODS: This prospective cohort study included current Kailuan Group employees and retirees who attended health checkups continuously from 2006 to 2010 and were followed up until December 31, 2021. A total of 56,129 individuals who completed the health checkups were selected and grouped according to coefficient of variation (CV) quartile for PPV. The standard deviation (SD) and variability independent of the mean were also calculated as measures of PPV. The cumulative incidence of fragility fracture in the four groups was calculated and the impact of PPV on the risk of fragility fracture was analyzed using a multivariate Cox regression model. The direction of the variation was also assessed. RESULTS: There were 671 cases of fragility fracture (1.2%) during a median follow-up of 11 years. In the multivariable-adjusted model, the hazard ratio for fragility fracture was 1.37 (95% confidence interval 1.11-1.70) for the highest CV quartile for PPV versus the lowest CV quartile for PPV. There was a linear association between higher PPV and fragility fracture. Consistent results were noted for higher PPV and the risk of fragility fracture using other indices of variability and in various sensitivity and subgroup analyses. CONCLUSIONS: High PPV was associated with a higher rate of fragility fracture independently of blood pressure. Reduction of PPV may help to prevent fragility fractures in the general population.

Recent advances in the identification of related factors and preventive strategies of hip fracture.

Hip fracture is the most devastating type of osteoporosis-related fracture, and is a major worldwide public health problem with a high socioeconomic burden, morbidity rate, and mortality rate. Thus, it is crucial to uncover the risk factors and protective factors to create a hip fracture prevention strategy. In addition to a briefly review of some well accepted risk and protective factors of hip fracture, this review mainly summarized the recent advances in the identification of emerging risk or protective factors for hip fracture, in terms of regional differences in medical services, diseases, drugs, mechanical load, neuromuscular mass, genes, blood types, cultural differences. This review provides a comprehensive review of the associated factors and effective prevention measures for hip fracture, and discusses issues that need further investigation. These issues include the determination of the influencing mechanism of risk factors triggering hip fracture and their interlinked correlation with other factors, as well as the confirmation or correction of emerging factors associated with hip fracture, particularly those that are still controversial. These recent findings will aid in optimizing the strategy for preventing hip fracture.

The fabrication and evaluation of silver nanoparticle-based keratin scaffolds.

The biotoxicity caused by focus releasing of Ag, which associated with the Ag loading mode, is a problematic issue that need to be solved for practical utilization of the keratin based wound dressing. In this study, keratin/AgNPs blend scaffolds (Ker/Ag) and keratin scaffolds with AgNPs attached on the scaffold's wall surface (Ag@Ker) were prepared. Structure and physical properties of the scaffolds were tested and investigated. In comparison to the Ag@Ker scaffolds, the Ker/Ag scaffolds with uniform dispersion of AgNPs have larger tensile strength and slower degradation rate. Both kind of scaffolds present excellent antibacterial property with 10 µg mL-1 AgNPs addition, while the Ker/Ag displayed a linear Ag releasing ratio in the first 5-7 days, which is beneficial for obtaining a continuous antibacterial property and avoiding the biotoxicity caused by focus release of Ag. Correspondingly, cytotoxicity assay further reveals that the continuously slow release of Ag of the Ker/Ag scaffolds accelerated the proliferation of cell. Infectious animal models and histological studies showed that the Ker/Ag scaffolds can effectively inhibit the inflammatory response and accelerate epithelialization. Thus, it can be concluded that the Ker/Ag scaffolds with uniform dispersion of AgNPs are more attractive as wound repair materials.

Carnosine and bone (Review).

Carnosine is a vital endogenous dipeptide that has anti­inflammatory, antiaging, anti­crosslinking, antitumor and immune regulatory effects. Numerous cell and animal model studies have proved that carnosine and its compounds promote the proliferation and differentiation of osteoblasts, inhibit osteoclasts and protect chondrocytes. They also regulate the cell cycle of bone progenitor cells and the differentiation of bone marrow mesenchymal stem cells, accelerate fracture healing, delay bone tumor development and ameliorate osteopenia induced by estrogen deficiency or disuse. The correlations between carnosine and activation signal molecules, pluripotent differentiation of bone marrow mesenchymal stem cells and interaction between bone cells are unclear. However, studies have proved that carnosine and its compounds have benefits in preventing and treating specific bone diseases. This makes them potential agents for the treatment of osteoporosis and bone tumors. The present review summarized the existing research on carnosine and its compounds in bone cells and tissue. It focused on the physiological function of carnosine and its compounds in the bone and their effect on bone metabolism­related diseases, thus providing support for developing new strategies for targeted therapy.