Unveiling the role of hypoxia-inducible factor 2alpha in osteoporosis:Implications for bone health

BACKGROUND Osteoporosis(OP)has become a major public health problem worldwide.Most OP treatments are based on the inhibition of bone resorption,and it is necessary to identify additional treatments aimed at enhancing osteogenesis.In the bone marrow(BM)niche,bone mesenchymal stem cells(BMSCs)are exposed to a hypoxic environment.Recently,a few studies have demonstrated that hypoxiainducible factor 2alpha(HIF-2α)is involved in BMSC osteogenic differentiation,but the molecular mechanism involved has not been determined.AIM To investigate the effect of HIF-2αon the osteogenic and adipogenic differentiation of BMSCs and the hematopoietic function of hematopoietic stem cells(HSCs)in the BM niche on the progression of OP.METHODS Mice with BMSC-specific HIF-2αknockout(Prx1-Cre;Hif-2αfl/fl mice)were used for in vivo experiments.Bone quantification was performed on mice of two genotypes with three interventions:Bilateral ovariectomy,semilethal irradiation,and dexamethasone treatment.Moreover,the hematopoietic function of HSCs in the BM niche was compared between the two mouse genotypes.In vitro,the HIF-2αagonist roxadustat and the HIF-2αinhibitor PT2399 were used to investigate the function of HIF-2αin BMSC osteogenic and adipogenic differentiation.Finally,we investigated the effect of HIF-2αon BMSCs via treatment with the mechanistic target of rapamycin(mTOR)agonist MHY1485 and the mTOR inhibitor rapamycin.RESULTS The quantitative index determined by microcomputed tomography indicated that the femoral bone density of Prx1-Cre;Hif-2αfl/fl mice was lower than that of Hif-2αfl/fl mice under the three intervention conditions.In vitro,Hif-2αfl/fl mouse BMSCs were cultured and treated with the HIF-2αagonist roxadustat,and after 7 d of BMSC adipogenic differentiation,the oil red O staining intensity and mRNA expression levels of adipogenesis-related genes in BMSCs treated with roxadustat were decreased;in addition,after 14 d of osteogenic differentiation,BMSCs treated with roxadustat exhibited increased expression of osteogenesis-related genes.The opposite effects were shown for mouse BMSCs treated with the HIF-2αinhibitor PT2399.The mTOR inhibitor rapamycin was used to confirm that HIF-2αregulated BMSC osteogenic and adipogenic differentiation by inhibiting the mTOR pathway.Consequently,there was no significant difference in the hematopoietic function of HSCs between Prx1-Cre;Hif-2αfl/fl and Hif-2αfl/fl mice.CONCLUSION Our study showed that inhibition of HIF-2αdecreases bone mass by inhibiting the osteogenic differentiation and increasing the adipogenic differentiation of BMSCs through inhibition of mTOR signaling in the BM niche.

Nonalcoholic fatty liver disease and cardiovascular disease

Nonalcoholic fatty liver disease(NAFLD)and cardiovascular disease(CVD)are two diseases that are common in the general population.To date,many studies have been conducted and demonstrate a direct link between NAFLD and CVD,but the exact mechanisms for this complex relationship are not well established.A systematic search of the PubMed database revealed that several common mechanisms are involved in many of the local and systemic manifestations of NAFLD and lead to an increased cardiovascular risk.The possible mechanisms linking NAFLD and CVD include inflammation,oxidative stress,insulin resistance,ectopic adipose tissue distribution,dyslipidemia,endothelial dysfunction,and adiponectin,among others.The clinical implication is that patients with NAFLD are at an increased risk of CVD and should undergo periodic cardiovascular risk assessment.

Diabetes patients with comorbidities had unfavorable outcomes following COVID-19:A retrospective study

BACKGROUND Previous studies have shown that diabetes mellitus is a common comorbidity of coronavirus disease 2019(COVID-19),but the effects of diabetes or anti-diabetic medication on the mortality of COVID-19 have not been well described.AIM To investigate the outcome of different statuses(with or without comorbidity)and anti-diabetic medication use before admission of diabetic after COVID-19.METHODS In this multicenter and retrospective study,we enrolled 1422 consecutive hospitalized patients from January 21,2020,to March 25,2020,at six hospitals in Hubei Province,China.The primary endpoint was in-hospital mortality.Epidemiological material,demographic information,clinical data,laboratory parameters,radiographic characteristics,treatment and outcome were extracted from electronic medical records using a standardized data collection form.Most of the laboratory data except fasting plasma glucose(FPG)were obtained in first hospitalization,and FPG was collected in the next day morning.Major clinical symptoms,vital signs at admission and comorbidities were collected.The treatment data included not only COVID-19 but also diabetes mellitus.The duration from the onset of symptoms to admission,illness severity,intensive care unit(ICU)admission,and length of hospital stay were also recorded.All data were checked by a team of sophisticated physicians.RESULTS Patients with diabetes were 10 years older than non-diabetic patients[(39-64)vs(56-70),P<0.001]and had a higher prevalence of comorbidities such as hypertension(55.5%vs 21.4%,P<0.001),coronary heart disease(CHD)(9.9%vs 3.5%,P<0.001),cerebrovascular disease(CVD)(3%vs 2.2%,P<0.001),and chronic kidney disease(CKD)(4.7%vs 1.5%,P=0.007).Mortality(13.6%vs 7.2%,P=0.003)was more prevalent among the diabetes group.Further analysis revealed that patients with diabetes who took acarbose had a lower mortality rate(2.2%vs 26.1,P<0.01).Multivariable Cox regression showed that male sex[hazard ratio(HR)2.59(1.68-3.99),P<0.001],hypertension[HR 1.75(1.18-2.60),P=0.006),CKD[HR 4.55(2.52-8.20),P<0.001],CVD[HR 2.35(1.27-4.33),P=0.006],and age were risk factors for the COVID-19 mortality.Higher HRs were noted in those aged≥65(HR 11.8[4.6-30.2],P<0.001)vs 50-64 years(HR 5.86[2.27-15.12],P<0.001).The survival curve revealed that,compared with the diabetes only group,the mortality was increased in the diabetes with comorbidities group(P=0.009)but was not significantly different from the noncomorbidity group(P=0.59).CONCLUSION Patients with diabetes had worse outcomes when suffering from COVID-19;however,the outcome was not associated with diabetes itself but with comorbidities.Furthermore,acarbose could reduce the mortality in diabetic.