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Tenofovir treatment of primary osteoblasts alters gene expression profiles: implications for bone mineral density loss.

ABSTRACT: There is strong clinical evidence that implicates tenofovir in the loss of bone mineral density during treatment of human immunodeficiency virus infection. In this study, we sought to test the hypothesis that tenofovir treatment of osteoblasts causes changes in the gene expression profile that would impact osteoblast function during bone formation. Primary osteoblasts were isolated and then treated with the tenofovir prodrug, tenofovir disoproxil fumarate (TDF). Total RNA from TDF-treated and untreated osteoblasts were extracted and used for microarray analysis to assess TDF-associated changes in the gene expression profile. Strikingly, the changes in gene expression profiles involved in cell signaling, cell cycle and amino acid metabolism, which would likely impact osteoblast function in bone formation. Our findings demonstrate for the first time that tenofovir treatment of primary osteoblasts results in gene expression changes that implicate loss of osteoblast function in tenofovir-associated bone mineral density loss.

SUBMITTER: Grigsby IF

PROVIDER: S-EPMC2847063 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Tenofovir treatment of primary osteoblasts alters gene expression profiles: implications for bone mineral density loss.

Grigsby Iwen F IF Pham Lan L Mansky Louis M LM Gopalakrishnan Raj R Carlson Ann E AE Mansky Kim C KC

Biochemical and biophysical research communications 20100218 1

There is strong clinical evidence that implicates tenofovir in the loss of bone mineral density during treatment of human immunodeficiency virus infection. In this study, we sought to test the hypothesis that tenofovir treatment of osteoblasts causes changes in the gene expression profile that would impact osteoblast function during bone formation. Primary osteoblasts were isolated and then treated with the tenofovir prodrug, tenofovir disoproxil fumarate (TDF). Total RNA from TDF-treated and un ...[more]

PMID: 20171173

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Project description:RATIONALE:Osteoporosis is common in individuals with chronic obstructive pulmonary disease. Lung-specific factors, including radiographic emphysema, independently associate with low bone mineral density in cross-sectional smoking cohorts. However, factors associated with progressive bone loss in smokers are understudied and largely unknown. OBJECTIVES:To determine the relationship between radiographic emphysema, circulating bone metabolism markers, and pulmonary function and accelerated bone mineral density loss in smokers. METHODS:Two hundred and forty male and female current and former smokers, 40 years of age or older, underwent baseline and 2-year assessments of pulmonary function, computed tomography-assessed emphysema, dual X-ray absorptiometry-measured bone mineral density, and circulating bone metabolism biomarker levels (type I collagen C-telopeptide [CTX], amino-terminal propeptide of type I procollagen [P1NP]). The association of radiographic emphysema, bone metabolism biomarker levels, and pulmonary function with accelerated hip bone mineral density loss, defined by the 75th percentile of annual hip bone mineral density decline, was determined by logistic regression modeling with adjustment for age, sex, inhaled and intermittent steroid use, active smoking, body mass index, and the presence of baseline low hip bone mineral density. RESULTS:Of those participants with accelerated hip bone mineral density loss, 22% had moderate or severe visually assessed emphysema compared with 7.2% of smokers without accelerated bone mineral density decline. Moderate to severe visually assessed emphysema (odds ratio, 2.84; 95% confidence interval, 1.01-7.98 compared with trace/mild or no visually assessed emphysema) and the 75th percentile of CTX levels (odds ratio, 2.38; 95% confidence interval, 1.20-4.72 compared with CTX levels below the 75th percentile), a marker of bone resorption, were associated with accelerated hip bone mineral density decline after adjustment for covariates and the presence of baseline low hip bone mineral density. FEV1% predicted was not associated with accelerated bone mineral density decline after adjustment for covariates. Multivariate modeling showed moderate to severe visually assessed emphysema, and the 75th percentiles of CTX were independently associated with accelerated hip bone mineral density decline after adjustment for covariates. CONCLUSIONS:Emphysema and elevated markers of bone resorption are independently associated with progressive bone mineral density loss in smokers. These clinical markers may guide targeted bone mineral density screening and monitoring in smokers at highest risk.

Project description:BackgroundSleeve gastrectomy is an effective bariatric procedure; however, sleeve gastrectomy-related adverse skeletal outcomes have been increasingly reported. High levels of sex hormone-binding globulin (SHBG) have been documented to be a risk factor of bone mineral density (BMD) loss with different effects observed between sexes. The aim of this study was to identify sex-specific changes in BMD following sleeve gastrectomy and to evaluate the role of SHBG in this process.MethodsThis retrospective study included 19 middle-aged men and 30 non-menopausal women with obesity who underwent sleeve gastrectomy in China. Anthropometrics, bone turnover markers, calciotropic hormones, BMD, SHBG, and gonadal steroids were measured preoperatively and at 6 and 12 months postoperatively. Longitudinal changes in BMD, bone turnover markers and SHBG were compared between sexes by linear mixed models. Multiple stepwise regression analysis was used to identify the predictors of BMD loss at the investigated bone sites.ResultsOver the 12-month study period, total hip and femoral neck BMD decreased, while lumbar spine BMD remained largely unchanged in both sexes. Linear mixed models revealed significant sex × time interaction effects in total hip BMD and SHBG, showing that men had a significantly greater reduction in total hip BMD and less increase in SHBG after sleeve gastrectomy than women. In the multivariate model, SHBG was significantly associated with total hip BMD loss in men (adjusted β = -0.533, P = 0.019) but not women while total estrogen was significantly associated with total hip BMD loss in women (adjusted β = 0.508, P = 0.01) but not men.ConclusionSignificant sex-specific BMD changes were observed after sleeve gastrectomy in the current study. Sleeve gastrectomy-related increase in SHBG may be a specific risk factor for total hip BMD loss in men. Our results indicate that sex-specific screening may be warranted to facilitate personalized postoperative bone care in this population.

Project description:BackgroundThe decrease of bone mineral density (BMD) after the intake of Tenofovir disoproxil fumarate (TDF)-based drugs in people living with HIV/AIDS (PLWHA) and HIV-negative key populations under pre-exposure prophylaxis (PrEP) regimen raised concerns. Previous findings on the effects of vitamin D (VD) and calcium supplements and the recovery of BMD loss were inconclusive. The optimal doses of VD and calcium and its supplementary duration remained unknown. Therefore, we conducted a systematic review and meta-analysis to synthesize current evidence on VD and calcium supplements to inform clinical practice.MethodsWe searched PubMed, Web of Science, Cochrane library, and EMBASE databases for all placebo-controlled trials and prospective cohort studies published before March 5, 2021 that investigated VD and calcium supplements in participants taking TDF-based drugs. The keywords calcium, vitamin D, Tenofovir, and BMD were used for the searches. The primary outcome was changes of spine and hip BMD. A subgroup analysis was performed to determine the factors that were related to the effects of VD supplements on BMD. Locally weighted regression (loess) was used to determine the relationships of VD supplements, supplementary duration, and changes of BMD. This study was registered at PROSPERO (No. 42021231000).FindingsSeven eligible studies including 703 participants were included in the analyses. The meta-analysis found that VD and calcium supplementation was related to a significant increase of BMD in the spine and hip [standardized mean difference (SMD) 0.43; 95% CI, 0.25 to 0.61, p = 0.009]. Moreover, positive dose-response relationships were demonstrated between doses of VD and calcium supplements, supplementary duration, and BMD recovery. Patients who took VD with the dose level of 4,000 IU/D obtained the highest BMD improvement (SMD 0.59, 95% CI, 0.43 to 0.74). No side effects were reported on VD and calcium supplementation.InterpretationWe found the VD and calcium supplementation was associated with increases of BMD in participants taking TDF-based drugs. An optimal supplementary dose of 4,000 IU/D for VD was suggested for clinicians. The findings could be used in clinical practice to improve the BMD outcomes in people who were taking TDF-based drugs.Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/.

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Tenofovir treatment of primary osteoblasts alters gene expression profiles: implications for bone mineral density loss.

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Tenofovir treatment of primary osteoblasts alters gene expression profiles: implications for bone mineral density loss.

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