Association with Longevity of Phosphatidylinositol 3-Kinase Regulatory Subunit 1 Gene Variants Stems from Protection against Mortality Risk in Men with Cardiovascular Disease

Gerontology ◽  
2021 ◽  
pp. 1-9
Author(s):  
Timothy A. Donlon ◽  
Randi Chen ◽  
Kamal H. Masaki ◽  
Bradley J. Willcox ◽  
Brian J. Morris
Keyword(s):  
Cardiovascular Disease ◽  
Life Span ◽  
Mortality Risk ◽  
Regulatory Subunit ◽  
Phosphatidylinositol 3 Kinase ◽  
Survival Curves ◽  
Genotypic Effect ◽  
Hazard Ratios ◽  
Phosphatidylinositol 3

<b><i>Introduction:</i></b> Genetic variation in the phosphatidylinositol 3-kinase reregulatory subunit 1 gene (<i>PIK3R1</i>) is associated with longevity. <b><i>Objective:</i></b> The aim of the study was to determine whether cardiovascular disease (CVD) affects this association. <b><i>Methods:</i></b> We performed a longitudinal study of longevity-associated <i>PIK3R1</i> single-nucleotide polymorphism <i>rs7709243</i> genotype by CVD status in 3,584 elderly American men of Japanese ancestry. <b><i>Results:</i></b> At baseline (1991–1993), 2,254 subjects had CVD and 1,314 did not. The follow-up until Dec 31, 2019 found that overall, men with a CVD had higher mortality than men without a CVD (<i>p</i> = 1.7 × 10<sup>−5</sup>). However, survival curves of CVD subjects differed according to <i>PIK3R1</i> genotype. Those with longevity-associated <i>PIK3R1 TT</i>/<i>CC</i> had survival curves similar to those of subjects without a CVD (<i>p</i> = 0.11 for <i>TT</i>/<i>CC</i>, and <i>p</i> = 0.054 for <i>TC</i>), whereas survival curves for CVD subjects with the <i>CT</i> genotype were significantly attenuated compared with survival curves of subjects without a CVD (<i>p</i> = 0.0000012 compared with <i>TT</i>/<i>CC</i>, and <i>p</i> = 0.0000028 compared with <i>TC</i>). Men without CVD showed no association of longevity-associated genotype with life span (<i>p</i> = 0.58). Compared to subjects without any CVD, hazard ratios for mortality risk were 1.26 (95% CI, 1.14–1.39; <i>p</i> = 0.0000043) for <i>CT</i> subject with CVD and 1.07 (95% CI 0.99–1.17; <i>p</i> = 0.097) for <i>CC</i>/<i>TT</i> subjects with CVD. There was no genotypic effect on life span for 1,007 subjects with diabetes and 486 with cancer. <b><i>Conclusion:</i></b> Our study provides novel insights into the basis for <i>PIK3R1</i> as a longevity gene. We suggest that the <i>PIK3R1</i> longevity genotype attenuates mortality risk in at-risk individuals by protection against cellular stress caused by CVD.

scholarly journals Estimates of mortality rates in people with diabetes and cardiovascular disease using administrative pharmaceutical data

2019 ◽  
Vol 4 (3) ◽  
Author(s):  
Shaun Purkiss ◽  
Tessa Keegel ◽  
Hassan Vally ◽  
Dennis Wollersheim
Keyword(s):  
Cardiovascular Disease ◽  
Mortality Risk ◽  
Age Groups ◽  
Mortality Rates ◽  
World Health ◽  
Data Set ◽  
Medication Discontinuation ◽  
Disease Mortality ◽  
Health Organization

BackgroundQuantifying the mortality risk for people with diabetes is challenging because of associated comorbidities. The recording of cause specific mortality from accompanying cardiovascular disease in death certificate notifications has been considered to underestimate the overall mortality risk in persons with diabetes. Main AimDevelop a technique to quantify mortality risk from pharmaceutical administrative data and apply it to persons diagnosed with diabetes, and associated cardiovascular disease and dyslipidaemia before death. MethodsPersons with diabetes, cardiovascular disease and dyslipidaemia were identified in a publicly available Australian Pharmaceutical data set using World Health Organization anatomic therapeutic codes assigned to medications received. Diabetes associated multi-morbidity cohorts were constructed and a proxy mortality (PM) event determined from medication and service discontinuation. Estimates of mortality rates were calculated from 2004 for 10 years and compared persons with diabetes alone and associated cardiovascular disease and dyslipidemia. ResultsThis study identified 346,201 individuals within the 2004 calendar year as having received treatments for diabetes (n=51,422), dyslipidaemia (n=169,323) and cardiovascular disease including hypertension (n=280,105). Follow up was 3.3 x 106 person-years. Overall crude PM was 26.1 per 1000 person-years. PM rates were highest in persons with cardiovascular disease and diabetes in combination (47.5 per 100 person years). Statin treatments significantly improved the mortality rates in all persons with diabetes and cardiovascular disease alone and in combination over age groups >44 years (p<.001). Age specific diabetes PM rates using pharmaceutical data correlated well with Australian data from the National Diabetes Service Scheme (r=0.82) ConclusionProxy mortality events calculated from medication discontinuation in persons with chronic conditions can provide an alternative method to estimate disease mortality rates. The technique also allows the assessment of mortality risk in persons with chronic disease multi-morbidity.

scholarly journals Phosphatidylinositol 3-kinase regulatory subunit 1 and phosphatase and tensin homolog as therapeutic targets in breast cancer

Tumor Biology ◽  
2017 ◽  
Vol 39 (3) ◽  
pp. 101042831769552 ◽  
Author(s):  
Ebubekir Dirican ◽  
Mustafa Akkiprik
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Breast Cancer Progression ◽  
Regulatory Subunit ◽  
Phosphatidylinositol 3 Kinase ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Kinase Pathway ◽  
Phosphatidylinositol 3

Breast cancer is the most commonly diagnosed cancer among women in Turkey and worldwide. It is considered a heterogeneous disease and has different subtypes. Moreover, breast cancer has different molecular characteristics, behaviors, and responses to treatment. Advances in the understanding of the molecular mechanisms implicated in breast cancer progression have led to the identification of many potential therapeutic gene targets, such as Breast Cancer 1/2, phosphatidylinositol 3-kinase catalytic subunit alpha, and tumor protein 53. The aim of this review is to summarize the roles of phosphatidylinositol 3-kinase regulatory subunit 1 (alpha) (alias p85α) and phosphatase and tensin homolog in breast cancer progression and the molecular mechanisms involved. Phosphatase and tensin homolog is a tumor suppressor gene and protein. Phosphatase and tensin homolog antagonizes the phosphatidylinositol 3-kinase/AKT signaling pathway that plays a key role in cell growth, differentiation, and survival. Loss of phosphatase and tensin homolog expression, detected in about 20%–30% of cases, is known to be one of the most common tumor changes leading to phosphatidylinositol 3-kinase pathway activation in breast cancer. Instead, the regulatory subunit p85α is a significant component of the phosphatidylinositol 3-kinase pathway, and it has been proposed that a reduction in p85α protein would lead to decreased negative regulation of phosphatidylinositol 3-kinase and hyperactivation of the phosphatidylinositol 3-kinase pathway. Phosphatidylinositol 3-kinase regulatory subunit 1 protein has also been reported to be a positive regulator of phosphatase and tensin homolog via the stabilization of this protein. A functional genetic alteration of phosphatidylinositol 3-kinase regulatory subunit 1 that results in reduced p85α protein expression and increased insulin receptor substrate 1 binding would lead to enhanced phosphatidylinositol 3-kinase signaling and hence cancer development. Phosphatidylinositol 3-kinase regulatory subunit 1 underexpression was observed in 61.8% of breast cancer samples. Therefore, expression/alternations of phosphatidylinositol 3-kinase regulatory subunit 1 and phosphatase and tensin homolog genes have crucial roles for breast cancer progression. This review will summarize the biological roles of phosphatidylinositol 3-kinase regulatory subunit 1 and phosphatase and tensin homolog in breast cancer, with an emphasis on recent findings and the potential of phosphatidylinositol 3-kinase regulatory subunit 1 and phosphatase and tensin homolog as a therapeutic target for breast cancer therapy.

scholarly journals Risk of early mortality and cardiovascular disease in type 1 diabetes: a comparison with type 2 diabetes, a nationwide study

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
You-Bin Lee ◽  
Kyungdo Han ◽  
Bongsung Kim ◽  
Seung-Eun Lee ◽  
Ji Eun Jun ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cardiovascular Disease ◽  
Type 1 Diabetes ◽  
Cox Regression ◽  
Early Mortality ◽  
Hazard Ratios ◽  
Epidemiological Characteristics

Abstract Background Both type 1 and type 2 diabetes are well-established risk factors for cardiovascular disease and early mortality. However, few studies have directly compared the hazards of cardiovascular outcomes and premature death among people with type 1 diabetes to those among people with type 2 diabetes and subjects without diabetes. Furthermore, information about the hazard of cardiovascular disease and early mortality among Asians with type 1 diabetes is sparse, although the clinical and epidemiological characteristics of Asians with type 1 diabetes are unlike those of Europeans. We estimated the hazard of myocardial infarction (MI), hospitalization for heart failure (HF), atrial fibrillation (AF), and mortality during follow-up in Korean adults with type 1 diabetes compared with those without diabetes and those with type 2 diabetes. Methods We used Korean National Health Insurance Service datasets of preventive health check-ups from 2009 to 2016 in this retrospective longitudinal study. The hazard ratios of MI, HF, AF, and mortality during follow-up were analyzed using the Cox regression analyses according to the presence and type of diabetes in ≥ 20-year-old individuals without baseline cardiovascular disease (N = 20,423,051). The presence and type of diabetes was determined based on the presence of type 1 or type 2 diabetes at baseline. Results During more than 93,300,000 person-years of follow-up, there were 116,649 MIs, 135,532 AF cases, 125,997 hospitalizations for HF, and 344,516 deaths. The fully-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for incident MI, hospitalized HF, AF, and all-cause death within the mean follow-up of 4.6 years were higher in the type 1 diabetes group than the type 2 diabetes [HR (95% CI) 1.679 (1.490–1.893) for MI; 2.105 (1.901–2.330) for HF; 1.608 (1.411–1.833) for AF; 1.884 (1.762–2.013) for death] and non-diabetes groups [HR (95% CI) 2.411 (2.138–2.718) for MI; 3.024 (2.730–3.350) for HF; 1.748 (1.534–1.993) for AF; 2.874 (2.689–3.073) for death]. Conclusions In Korea, the presence of diabetes was associated with a higher hazard of cardiovascular disease and all-cause death. Specifically, people with type 1 diabetes had a higher hazard of cardiovascular disease and all-cause mortality compared to people with type 2 diabetes.

scholarly journals Menstrual cycle regularity and length across the reproductive lifespan and risk of premature mortality: prospective cohort study

BMJ ◽  
2020 ◽  
pp. m3464 ◽  
Author(s):  
Yi-Xin Wang ◽  
Mariel Arvizu ◽  
Janet W Rich-Edwards ◽  
Jennifer J Stuart ◽  
JoAnn E Manson ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Cohort Study ◽  
Prospective Cohort Study ◽  
Prospective Cohort ◽  
Cycle Length ◽  
Premature Mortality ◽  
Health Study ◽  
Menstrual Cycles ◽  
Hazard Ratios

AbstractObjectiveTo evaluate whether irregular or long menstrual cycles throughout the life course are associated with all cause and cause specific premature mortality (age <70 years).DesignProspective cohort study.SettingNurses’ Health Study II (1993-2017).Participants79 505 premenopausal women without a history of cardiovascular disease, cancer, or diabetes and who reported the usual length and regularity of their menstrual cycles at ages 14-17 years, 18-22 years, and 29-46 years.Main outcome measuresHazard ratios and 95% confidence intervals for all cause and cause specific premature mortality (death before age 70 years) were estimated from multivariable Cox proportional hazards models.ResultsDuring 24 years of follow-up, 1975 premature deaths were documented, including 894 from cancer and 172 from cardiovascular disease. Women who reported always having irregular menstrual cycles experienced higher mortality rates during follow-up than women who reported very regular cycles in the same age ranges. The crude mortality rate per 1000 person years of follow-up for women reporting very regular cycles and women reporting always irregular cycles were 1.05 and 1.23 for cycle characteristics at ages 14-17 years, 1.00 and 1.37 for cycle characteristics at ages 18-22 years, and 1.00 and 1.68 for cycle characteristics at ages 29-46 years. The corresponding multivariable adjusted hazard ratios for premature death during follow-up were 1.18 (95% confidence interval 1.02 to 1.37), 1.37 (1.09 to 1.73), and 1.39 (1.14 to 1.70), respectively. Similarly, women who reported that their usual cycle length was 40 days or more at ages 18-22 years and 29-46 years were more likely to die prematurely than women who reported a usual cycle length of 26-31 days in the same age ranges (1.34, 1.06 to 1.69; and 1.40, 1.17 to 1.68, respectively). These relations were strongest for deaths related to cardiovascular disease. The higher mortality associated with long and irregular menstrual cycles was slightly stronger among current smokers.ConclusionsIrregular and long menstrual cycles in adolescence and adulthood are associated with a greater risk of premature mortality (age <70 years). This relation is slightly stronger among women who smoke.

Tea consumption and the risk of atherosclerotic cardiovascular disease and all-cause mortality: The China-PAR project

2020 ◽  
Vol 27 (18) ◽  
pp. 1956-1963 ◽  
Author(s):  
Xinyan Wang ◽  
Fangchao Liu ◽  
Jianxin Li ◽  
Xueli Yang ◽  
Jichun Chen ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Disease Incidence ◽  
Atherosclerotic Cardiovascular Disease ◽  
Tea Consumption ◽  
Hazard Ratios ◽  
Disease Mortality ◽  
All Cause Mortality ◽  
Cox Proportional Hazard Regression ◽  
Study Participants

Aims The role of tea consumption in the primary prevention of atherosclerotic cardiovascular disease remains unclear in cohort studies. This prospective cohort study aimed to investigate the associations of tea consumption with the risk of atherosclerotic cardiovascular disease and all-cause mortality. Methods We included 100,902 general Chinese adults from the project of Prediction for ASCVD Risk in China (China-PAR) in 15 provinces across China since 1998. Information on tea consumption was collected through standardized questionnaires. Outcomes were identified by interviewing study participants or their proxies, and checking hospital records and/or death certificates. Cox proportional hazard regression models were used to calculate hazard ratios and their corresponding 95% confidence intervals related to tea consumption. Results During a median follow-up of 7.3 years, 3683 atherosclerotic cardiovascular disease events, 1477 atherosclerotic cardiovascular disease deaths, and 5479 all-cause deaths were recorded. Compared with never or non-habitual tea drinkers, the hazard ratio and 95% confidence interval among habitual tea drinkers was 0.80 (0.75–0.87), 0.78 (0.69–0.88), and 0.85 (0.79–0.90) for atherosclerotic cardiovascular disease incidence, atherosclerotic cardiovascular disease mortality, and all-cause mortality, respectively. Habitual tea drinkers had 1.41 years longer of atherosclerotic cardiovascular disease-free years and 1.26 years longer of life expectancy at the index age of 50 years. The observed inverse associations were strengthened among participants who kept the habit during the follow-up period. Conclusion Tea consumption was associated with reduced risks of atherosclerotic cardiovascular disease and all-cause mortality, especially among those consistent habitual tea drinkers.

scholarly journals Lp(a) (Lipoprotein[a]) Concentrations and Incident Atherosclerotic Cardiovascular Disease

2020 ◽  
Author(s):  
Aniruddh P. Patel ◽  
Minxian Wang ◽  
James P. Pirruccello ◽  
Patrick T. Ellinor ◽  
Kenney Ng ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
South Asian ◽  
Clinical Importance ◽  
Atherosclerotic Cardiovascular Disease ◽  
Middle Aged ◽  
Lipoprotein A ◽  
Hazard Ratios ◽  
Middle Aged Adults ◽  
Relationship Of

Objective: Lipoprotein(a) concentrations are associated with atherosclerotic cardiovascular disease (ASCVD), and new therapies that enable potent and specific reduction are in development. In the largest study conducted to date, we address 3 areas of uncertainty: (1) the magnitude and shape of ASCVD risk conferred across the distribution of lipoprotein(a) concentrations; (2) variation of risk across racial and clinical subgroups; (3) clinical importance of a high lipoprotein(a) threshold to guide therapy. Approach and Results: Relationship of lipoprotein(a) to incident ASCVD studied in 460 506 middle-aged UK Biobank participants. Over a median follow-up of 11.2 years, incident ASCVD occurred in 22 401 (4.9%) participants. Median lipoprotein(a) concentration was 19.6 nmol/L (25th–75th percentile 7.6–74.8). The relationship between lipoprotein(a) and ASCVD appeared linear across the distribution, with a hazard ratio of 1.11 (95% CI, 1.10–1.12) per 50 nmol/L increment. Substantial differences in concentrations were noted according to race—median values for white, South Asian, black, and Chinese individuals were 19, 31, 75, and 16 nmol/L, respectively. However, risk per 50 nmol/L appeared similar—hazard ratios of 1.11, 1.10, and 1.07 for white, South Asian, and black individuals, respectively. A high lipoprotein(a) concentration defined as ≥150 nmol/L was present in 12.2% of those without and 20.3% of those with preexisting ASCVD and associated with hazard ratios of 1.50 (95% CI, 1.44–1.56) and 1.16 (95% CI, 1.05–1.27), respectively. Conclusions: Lipoprotein(a) concentrations predict incident ASCVD among middle-aged adults within primary and secondary prevention contexts, with a linear risk gradient across the distribution. Concentrations are variable across racial subgroups, but the associated risk appears similar.

scholarly journals A population-based study of cardiovascular disease mortality risk in US cancer patients

2019 ◽  
Vol 40 (48) ◽  
pp. 3889-3897 ◽  
Author(s):  
Kathleen M Sturgeon ◽  
Lei Deng ◽  
Shirley M Bluethmann ◽  
Shouhao Zhou ◽  
Daniel M Trifiletti ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Heart Disease ◽  
General Population ◽  
Cancer Diagnosis ◽  
Mortality Risk ◽  
First Year ◽  
Cardiovascular Disease Mortality ◽  
Disease Mortality ◽  
Cvd Mortality

Abstract Aims This observational study characterized cardiovascular disease (CVD) mortality risk for multiple cancer sites, with respect to the following: (i) continuous calendar year, (ii) age at diagnosis, and (iii) follow-up time after diagnosis. Methods and results The Surveillance, Epidemiology, and End Results program was used to compare the US general population to 3 234 256 US cancer survivors (1973–2012). Standardized mortality ratios (SMRs) were calculated using coded cause of death from CVDs (heart disease, hypertension, cerebrovascular disease, atherosclerosis, and aortic aneurysm/dissection). Analyses were adjusted by age, race, and sex. Among 28 cancer types, 1 228 328 patients (38.0%) died from cancer and 365 689 patients (11.3%) died from CVDs. Among CVDs, 76.3% of deaths were due to heart disease. In eight cancer sites, CVD mortality risk surpassed index-cancer mortality risk in at least one calendar year. Cardiovascular disease mortality risk was highest in survivors diagnosed at &lt;35 years of age. Further, CVD mortality risk is highest (SMR 3.93, 95% confidence interval 3.89–3.97) within the first year after cancer diagnosis, and CVD mortality risk remains elevated throughout follow-up compared to the general population. Conclusion The majority of deaths from CVD occur in patients diagnosed with breast, prostate, or bladder cancer. We observed that from the point of cancer diagnosis forward into survivorship cancer patients (all sites) are at elevated risk of dying from CVDs compared to the general US population. In endometrial cancer, the first year after diagnosis poses a very high risk of dying from CVDs, supporting early involvement of cardiologists in such patients.

4949Diverging secular trends in cardiovascular disease 21-year incidence in Swedish men born in 1950–1978

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
D Aberg ◽  
M Adiels ◽  
M Lindgren ◽  
J Nyberg ◽  
G Kuhn ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Cardiovascular Disease ◽  
Military Service ◽  
Secular Trends ◽  
Longitudinal Change ◽  
Medical Society ◽  
Hazard Ratios ◽  
Cox Proportional Hazard Models

Abstract Background Cardiovascular disease (CVD) mortality is decreasing in Western countries, including Sweden. However, there are reports of increases in incidence in young people with respect to heart failure (HF) and atrial fibrillation (AF). The magnitude and causes of these changes are only partly known. Aims We investigated secular trends in incidence in CVD outcomes and their attenuation by changes in body mass index (BMI). The outcomes were risk of acute myocardial infarction (AMI), heart failure (HF) and atrial fibrillation (AF) as well as cardiovascular and all-cause death in a population of Swedish adolescents. Methods We followed a cohort of Swedish men enrolled for military service conscription in 1969–1996 (n=1,326,082; mean age=18.3) until December 2016, collected from the national inpatient (IPR) and outpatient registries (OPR). Cox-proportional hazard models were used to analyse the longitudinal change in incidence by with respect to early (0–21 years) of follow-up for subgroups with conscription 1968–1971, 1971–1976, 1976–1981, 1981–1986, 1986–1991, 1991–1996 (with the group born 1971–1976 as reference). Adjustments for potential confounders including BMI were performed. Results We found that CVD and all-cause mortality and MI decreased progressively during the follow-up with hazard ratios (HR) of 0.51, 95% confidence interval (CI) 0.43–0.62, HR 0.51 CI 0.57–0.62, and 0.60 CI 0.50–0.72, respectively. In contrast, we found increases in the incidence of HF (HR 1.86, CI 1.48–2.33], and AF (HR 8.26, CI 6.87–9.92). Adjustments for changes in BMI partly attenuated the changes in secular trends. Cubic spline models showed where the changes in secular trends were most prominent. Conclusion The incidences of cardiovascular outcomes show diverging secular changes. While MI and cardiovascular mortality are continually decreasing, there is an increase in HF and AF. The associations appear to be partly explained by changes in index BMI over time. Acknowledgement/Funding grants from the Swedish Government and the county councils, the ALF–GBG-719761, ALFGBG-751111, Swedish Stroke Association, Göteborg Medical Society

scholarly journals Statin-induced Ras Activation Integrates the Phosphatidylinositol 3-Kinase Signal to Akt and MAPK for Bone Morphogenetic Protein-2 Expression in Osteoblast Differentiation

2006 ◽  
Vol 282 (7) ◽  
pp. 4983-4993 ◽  
Author(s):  
Nandini Ghosh-Choudhury ◽  
Chandi Charan Mandal ◽  
Goutam Ghosh Choudhury
Keyword(s):  
Bone Morphogenetic Protein ◽  
Osteoblast Differentiation ◽  
Dominant Negative ◽  
Bone Morphogenetic Protein 2 ◽  
Regulatory Subunit ◽  
Type I ◽  
Dependent Manner ◽  
Phosphatidylinositol 3 Kinase ◽  
Morphogenetic Protein ◽  
Phosphatidylinositol 3

Lovastatin promotes osteoblast differentiation by increasing bone morphogenetic protein-2 (BMP-2) expression. We demonstrate that lovastatin stimulates tyrosine phosphorylation of the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3K), leading to an increase in its kinase activity in osteoblast cells. Inhibition of PI3K ameliorated expression of the osteogenic markers alkaline phosphatase, type I collagen, osteopontin, and BMP-2. Expression of dominant-negative PI3K and PTEN, an inhibitor of PI3K signaling, significantly attenuated lovastatin-induced transcription of BMP-2. Akt kinase was also activated in a PI3K-dependent manner. However, our data suggest involvement of an additional signaling pathway. Lovastatin-induced Erk1/2 activity contributed to BMP-2 transcription. Inhibition of PI3K abrogated Erk1/2 activity in response to lovastatin, indicating the presence of a signal relay between them. We provide, as a mechanism of this cross-talk, the first evidence that lovastatin stimulates rapid activation of Ras, which associates with and activates PI3K in the plasma membrane, which in turn regulates Akt and Erk1/2 to induce BMP-2 expression for osteoblast differentiation.

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