Elevated Growth Differentiation Factor 15 Research Articles

GDF-15 and mtDNA Deletions Are Useful Biomarkers of Mitochondrial Dysfunction in Insulin Resistance and PCOS.

There is no literature available about the growth differentiation factor-15 (GDF-15) biomarker in combination with mitochondrial DNA (mtDNA) deletions in insulin resistance (IR), and polycystic ovary syndrome (PCOS); however, it would be useful to achieve optimal metabolic status and improve pregnancy success. In this study, the role of GDF-15 and mtDNA deletions as biomarkers in the pathogenesis of IR and PCOS was investigated. In our study, 81 female patients who were treated for IR and/or PCOS and 41 healthy controls were included. GDF-15 levels in patients showed a marked increase compared to controls. Elevated GDF-15 levels were found in 12 patients; all of them had a BMI > 25 kg/m2, which is associated with reactive hyperinsulinemia. The presence of mitochondrial dysfunction was mainly observed in the IR-only subgroup. The increase in plasma levels of GDF-15 and the prevalence of mtDNA deletions is directly proportional to body mass index. The more marked metabolic abnormalities required more intensive drug therapy with a parallel increase in plasma GDF-15 levels. Elevated levels of GDF-15 and the presence of mitochondrial DNA deletions may be a consequence of carbohydrate metabolism disorders in patients and thus a predictor of the process of accelerated aging.

Elevated serum GDF15 level as an early indicator of proximal tubular cell injury in acute kidney injury

Acute kidney injury (AKI) is a high-burden medical condition, and current diagnostic criteria can only assess AKI after full manifestation. Stress marker growth differentiation factor 15 (GDF15) was reported to have a role in kidney injury of critical patients. Herein, we evaluated dynamic changes in GDF15 across diverse AKI scenarios and explored the underlying mechanisms of its induction. Serum parameters and renal lesions were analyzed in mouse models of unilateral ischemia-reperfusion injury (uni-IRI) and unilateral ureteral obstruction (UUO). The human proximal tubular (HK−2) cell line was stimulated with various conditions, and induction of GDF15 expression was determined. Serum GDF15 levels were rapidly induced within hours after injury in both animal models and declined thereafter. Renal GDF15 expression exhibited a temporary and early increased induction and was mainly located in aquaporin 1-positive proximal tubules in both unilateral AKI model tissues. In cell experiments, rapid GDF15 production was highly induced by t-BHP and CoCl2. Treatment with either an antioxidant or mitogen-activated protein kinase inhibitors abolished t-BHP- and CoCl2-mediated GDF15 expression. In addition, silencing nuclear factor erythroid 2-related factor 2 expression also reduced the basal and t-BHP- or CoCl2-mediated GDF15 expression level in HK-2 cells. Our data showed that elevated serum GDF15 levels could be detected early in unilateral AKI models without notable alterations in kidney function parameters. GDF15 expression was associated with oxidative stress- and hypoxia-mediated proximal tubular cell injury. These data document that elevated serum GDF15 can possibly serve as an early biomarker for proximal tubular cell injury in AKI.

ATF4-dependent and independent mitokine secretion from OPA1 deficient skeletal muscle in mice is sexually dimorphic.

Reducing Optic Atrophy 1 (OPA1) expression in skeletal muscle in male mice induces Activation Transcription Factor 4 (ATF4) and the integrated stress response (ISR). Additionally, skeletal muscle secretion of Fibroblast Growth Factor 21 (FGF21) is increased, which mediates metabolic adaptations including resistance to diet-induced obesity (DIO) and glucose intolerance in these mice. Although FGF21 induction in this model can be reversed with pharmacological attenuation of ER stress, it remains to be determined if ATF4 is responsible for FGF21 induction and its metabolic benefits in this model. We generated mice with homozygous floxed Opa1 and Atf4 alleles and a tamoxifen-inducible Cre transgene controlled by the human skeletal actin promoter to enable simultaneous depletion of OPA1 and ATF4 in skeletal muscle (mAO DKO). Mice were fed high fat (HFD) or control diet and evaluated for ISR activation, body mass, fat mass, glucose tolerance, insulin tolerance and circulating concentrations of FGF21 and growth differentiation factor 15 (GDF15). In mAO DKO mice, ATF4 induction is absent. Other indices of ISR activation, including XBP1s, ATF6, and CHOP were induced in mAO DKO males, but not in mOPA1 or mAO DKO females. Resistance to diet-induced obesity was not reversed in mAO DKO mice of both sexes. Circulating FGF21 and GDF15 illustrated sexually dimorphic patterns. Loss of OPA1 in skeletal muscle increases circulating FGF21 in mOPA1 males, but not in mOPA1 females. Additional loss of ATF4 decreased circulating FGF21 in mAO DKO male mice, but increased circulating FGF21 in female mAO DKO mice. Conversely, circulating GDF15 was increased in mAO DKO males and mOPA1 females, but not in mAO DKO females. Sex differences exist in the transcriptional outputs of the ISR following OPA deletion in skeletal muscle. Deletion of ATF4 in male and female OPA1 KO mice does not reverse the resistance to DIO. Induction of circulating FGF21 is ATF4 dependent in males, whereas induction of circulating GDF15 is ATF4 dependent in females. Elevated GDF15 in males and FGF21 in females could reflect activation by other transcriptional outputs of the ISR, that maintain mitokine-dependent metabolic protection in an ATF4-independent manner.

Ponsegromab for the Treatment of Cancer Cachexia.

Cachexia is a common complication of cancer and is associated with an increased risk of death. The level of growth differentiation factor 15 (GDF-15), a circulating cytokine, is elevated in cancer cachexia. In a small, open-label, phase 1b study involving patients with cancer cachexia, ponsegromab, a humanized monoclonal antibody inhibiting GDF-15, was associated with improved weight, appetite, and physical activity, along with suppressed serum GDF-15 levels. In this phase 2, randomized, double-blind, 12-week trial, we assigned patients with cancer cachexia and an elevated serum GDF-15 level (≥1500 pg per milliliter) in a 1:1:1:1 ratio to receive ponsegromab at a dose of 100 mg, 200 mg, or 400 mg or to receive placebo, administered subcutaneously every 4 weeks for three doses. The primary end point was the change from baseline in body weight at 12 weeks. Key secondary end points were appetite and cachexia symptoms, digital measures of physical activity, and safety. A total of 187 patients underwent randomization. Of these patients, 40% had non-small-cell lung cancer, 32% had pancreatic cancer, and 29% had colorectal cancer. At 12 weeks, patients in the ponsegromab groups had significantly greater weight gain than those in the placebo group, with a median between-group difference of 1.22 kg (95% credible interval, 0.37 to 2.25) in the 100-mg group, 1.92 (95% credible interval, 0.92 to 2.97) in the 200-mg group, and 2.81 (95% credible interval, 1.55 to 4.08) in the 400-mg group. Improvements were observed across measures of appetite and cachexia symptoms, along with physical activity, in the 400-mg ponsegromab group relative to placebo. Adverse events of any cause were reported in 70% of the patients in the ponsegromab group and in 80% of those in the placebo group. Among patients with cancer cachexia and elevated GDF-15 levels, the inhibition of GDF-15 with ponsegromab resulted in increased weight gain and overall activity level and reduced cachexia symptoms, findings that confirmed the role of GDF-15 as a driver of cachexia. (Funded by Pfizer; ClinicalTrials.gov number, NCT05546476.).

GDF15 attenuates sepsis-induced myocardial dysfunction by inhibiting cardiomyocytes ferroptosis via the SOCS1/GPX4 signaling pathway

Sepsis is a systemic inflammatory response syndrome triggered by infection, presenting with symptoms such as fever, increased heart rate, and low blood pressure. In severe cases, it can lead to multiple organ dysfunction, posing a life-threatening risk. Sepsis-induced cardiomyopathy (SIC) is a critical factor in the poor prognosis of septic patients, leading to myocardial dysfunction characterized by cell death, inflammation, and diminished cardiac function. Ferroptosis, an iron-dependent form of programmed cell death, is a key mechanism causing cardiomyocyte damage in SIC. Growth differentiation factor 15 (GDF15), a member of the TGF-β superfamily, is associated with various cardiovascular diseases and can inhibit oxidative stress, reduce reactive oxygen species (ROS), and suppress ferroptosis. Elevated serum GDF15 levels in sepsis are correlated with organ injuries, suggesting its potential as a therapeutic target. However, its role and mechanisms in SIC remain unclear. Glutathione peroxidase 4 (GPX4), the only enzyme capable of reducing lipid peroxides within cells, protects cells by reducing lipid peroxidation levels and inhibiting ferroptosis. Investigating the regulatory factors of GPX4 may provide a theoretical basis for SIC treatment. In this study, a mouse SIC model revealed that elevated GDF15 exerts a protective effect. Antagonizing GDF15 exacerbates myocardial damage. Through transcriptomic analysis and other methods, we confirmed that GDF15 inhibits the expression of SOCS1 by activating the ALK5-SMAD2/3 pathway, thereby activates the JAK2/STAT3 pathway, promotes the transcription of GPX4, inhibits ferroptosis in cardiomyocytes, and plays a myocardial protective role in SIC.

Growth Differentiation Factor-15 Is Considered a Predictive Biomarker of Long COVID in Non-hospitalized Patients.

Mitochondrial dysfunction is associated with various diseases. Mitochondria plays a regulatory role during infection. The association between mitokines and subsequent COVID progression has not been previously studied. The retrospective cohort study aimed to investigate the potential of serum mitokines as long COVIDbiomarkers in non-hospitalized patients. Patients with confirmed SARS-CoV-2 infection and blood test reports between January 2021 and April 2023 were included. Patients were categorized into two groups, the recovered and long COVID groups, based on fatigue, decline in focus, and pain. Serum levels of growth differentiation factor 15 (GDF-15) and fibroblast growth factor-21 (FGF-21), which are affected by mitochondrial function, along with inflammatory and vascular endothelium markers, were measured using enzyme-linked immunosorbent assays (ELISA). A receiver operating characteristic curve was used to screen the biomarkers. The threshold value of GDF-15 in the acute phase was 965 pg/mL (sensitivity: 71.4%, specificity: 83.3%), indicating that GDF-15 may be associated with the presence of symptoms three months post onset. No association with inflammatory markers and vascular structures was observed. Therefore, elevated GDF-15 levels in the acute phase may act as a predictive biomarker of long COVID.

Prognostic value of growth differentiation factor-15 in heart failure among whole ejection fraction phenotypes.

The utility of growth differentiation factor-15 (GDF-15) in predicting long-term adverse outcomes in heart failure (HF) patients is not well established. This study explored the relationship between GDF-15 levels and adverse outcomes in HF patients across various ejection fraction (EF) phenotypes associated with coronary heart disease (CHD) and evaluated the added prognostic value of incorporating GDF-15 into the Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) risk score-based model. This single-centre cohort study included 823 HF patients, categorized into 230 (27.9%) reduced EF (HFrEF), 271 (32.9%) mid-range EF (HFmrEF), and 322 (39.1%) preserved EF (HFpEF) groups. The median age was 68.0years (range: 56.0-77.0), and 245 (29.8%) were females. Compared with the HFrEF and HFmrEF groups, the HFpEF group had a higher GDF-15 concentration (P=0.002) and a higher MAGGIC risk score (P<0.001). We examined the associations between GDF-15 levels and the risks of all-cause mortality and HF rehospitalization using Cox regression models. The C-index, integrated discrimination improvement (IDI), and net reclassification improvement (NRI) metrics were employed to assess the incremental prognostic value. During the 9.4year follow-up period, 425 patients died, and 484 were rehospitalized due to HF. Multivariate Cox regression analysis revealed that elevated GDF-15 levels were significantly associated with an increased risk of all-cause mortality [hazard ratio (HR)=1.36, 95% confidence interval (CI): 1.20-1.54; P<0.001] and HF rehospitalization (HR=1.75, 95% CI: 1.57-1.95; P<0.001) across all HF phenotypes. This association remained significant when GDF-15 was treated as a categorical variable (high GDF-15 group: all-cause death: HR=1.73, 95% CI: 1.40-2.14; P<0.001; HF rehospitalization: HR=3.37, 95% CI: 2.73-4.15; P<0.001). Inclusion of GDF-15 in the MAGGIC risk score-based model provided additional prognostic value for all HF patients (Δ C-index=0.021, 95% CI: 0.002-0.041; IDI=0.011, 95% CI: 0.001-0.025; continuous NRI=0.489, 95% CI: 0.174-0.629) and HF rehospitalization (Δ C-index=0.034, 95% CI: 0.005-0.063; IDI=0.021, 95% CI: 0.007-0.032; continuous NRI=0.307, 95% CI: 0.147-0.548), particularly in the HFpEF subgroup. GDF-15 is identified as an independent risk factor for adverse outcomes in HF patients across the entire EF spectrum in the context of CHD. Integrating GDF-15 into the MAGGIC risk score-based model enhances its prognostic capability for adverse outcomes in the general HF population. This incremental prognostic effect was observed specifically in the HFpEF subgroup and not in other subgroups.

Knockdown of growth differentiation factor-15 restrains prostate cancer through regulating MAPK/ERK signaling pathway.

Prostate cancer, prevalent among males, is influenced by various molecular factors, including Growth Differentiation Factor 15 (GDF15). Despite its recognized role in multiple tumor types, GDF15's specific involvement in prostate cancer remains insufficiently explored. This study investigates the regulatory function of GDF15 in prostate cancer. To explore GDF15's impact, we established GDF15 knockdown and overexpression models in prostate cancer cells. We quantified mRNA and protein levels using RT-PCR and Western blotting. Functional assays, including CCK8, Transwell, wound healing, and flow cytometry, were employed to evaluate cell proliferation, invasion, migration, and apoptosis. Additionally, the effect of GDF15 on tumor growth was assessed using a metastatic tumor model in nude mice. Elevated GDF15 expression was identified in prostate cancer tissues and cells. The knockdown of GDF15 led to the activation of the MAPK/ERK signaling pathway. C16PAF was found to counteract the inhibitory effects of sh-GDF15 on cell proliferation, invasion, migration, and apoptosis in LNCaP cells. It also reversed the sh-GDF15-induced alterations in the epithelial-mesenchymal transition (EMT) process. In vivo, C16PAF notably mitigated the sh-GDF15-induced suppression of tumor growth. The study demonstrated that sh-GDF15 inhibits cell proliferation, invasion, migration, EMT process, and tumor growth, while it promotes apoptosis. However, these effects were significantly reversed by C16PAF. The study underscores the potential of GDF15 as a target for novel therapeutic interventions in prostate cancer treatment and prevention. These findings illuminate GDF15's multifaceted role in prostate cancer pathogenesis and suggest its viability as a therapeutic target.

Growth Differentiation Factor 15 and Diet Quality Trajectory Interact to Determine Frailty Incidence among Middle-Aged Urban Adults

BackgroundElevated plasma growth differentiation factor 15 (GDF15) and poor diet quality may be associated with increased frailty incidence, although their interactive associations have not been assessed in urban middle-aged adults. ObjectivesWe aimed to examine GDF15 and its interactive association with diet quality in relation to frailty incidence among a sample of middle-aged urban adults. MethodsThe relationship between GDF15 and diet quality trajectories in relation to incident frailty was examined in a longitudinal study of participants in the Healthy Aging in Neighborhoods of Diversity across the Life Span (2004–2017). Serum GDF15 concentration and frailty incidence were primary exposure and outcome, respectively. Group-based trajectory models were used to assess diet quality trajectories (≤3 visits/participant, N = 945, N′ = 2247 observations) using the Healthy Eating Index 2010 version (HEI-2010), Dietary Inflammatory Index, and mean adequacy ratio (MAR). Cox proportional hazards models were used, testing interactive associations of GDF15 and diet quality trajectories with frail/prefrail incidence (N = 400 frailty-free at first visit, N′ = 604 observations, n = 168 incident frail/prefrail). ResultsBoth elevated GDF15 and lower diet quality trajectories were associated with a lower probability of remaining nonfrail (≤13 y follow-up). Among females, the “high diet quality” HEI-2010 trajectory had a hazard ratio (HR) of 0.15 [95% confidence interval (CI): 0.04, 0.54; P = 0.004; fully adjusted model] when compared with the “low diet quality” trajectory group. Among males only, there was an antagonistic interaction between lower HEI-2010 trajectory and elevated GDF15. Specifically, the HR for GDF15-frailty in the higher diet quality trajectory group (high/medium combined), and among males, was 2.69 (95% CI: 1.06, 6.62; P = 0.032), whereas among the lower diet quality trajectory group, the HR was 0.94 (95% CI: 0.49, 1.80; P = 0.86). Elevated GDF15 was independently associated with frailty among African American adults. ConclusionsPending replication, we found an antagonistic interaction between GDF15 and HEI-2010 trajectory in relation to frailty incidence among males.

GDF15 AND REDUCED PHYSICAL FUNCTION FOLLOWING TOTAL KNEE REPLACEMENT: A STUDY OF PHYSICAL RESILIENCE AND AGING

Abstract The metabolic and inflammatory cytokine growth-differentiation factor 15 (GDF15) increases with age and negatively associates with physical and cognitive function in older adults. We hypothesized GDF15 also negatively associates with resilient outcomes after surgery. This hypothesis was tested in the SPRING study of physical resiliency after total knee replacement by assessing relationships between pre-operative plasma GDF15 levels and postoperative resilience measures including short physical performance battery (SPPB) scores, fatigability, and grip strength. GDF15 analyses and physical resilience were assessed in 127 SPRING participants (age 70±6 yrs, n=83 women). Baseline GDF15 levels correlated with age (r=0.263, P&amp;lt; 0.05); age-adjusted analyses were applied. In total, pre-operative GDF15 levels did not significantly correlate with functional measures at any timepoint. However, in men (n=44), GDF15 levels correlated with age (r=0.408, P&amp;lt; 0.05) and significant age-adjusted correlations were observed in fatigue (r=0.368, P&amp;lt; 0.05), gait speed (r=-0.428, P&amp;lt; 0.05), and SPPB score (r=-0.329, P&amp;lt; 0.05). Additionally, GDF15 levels correlated with chair stands at six months (r=-0.398, P&amp;lt; 0.05), SPPB score at six months (r=-0.384, P&amp;lt; 0.05), and gait speed after one year (r=-0.487, P&amp;lt; 0.05). GDF15 did not significantly correlate with changes in SPPB score (P&amp;gt;0.05). There were no significant correlations between GDF15 and any of these functional measures in women (r-value range: -0.259 to 0.107; p-value range: 0.112 to 0.969). Elevated pre-operative GDF15 appears to correlate with worsening physical function following knee replacement in men, but not women. Further investigation is necessary to understand the relationship between GDF15 and the biology of physical resiliency.

Abstract 16679: Growth Differentiation Factor 15 in the Initial Evaluation of Suspected Coronary Artery Disease

Introduction: The cytokine growth differentiation factor 15 (GDF-15) is expressed in several tissues including cardiomyocytes, and is up-regulated in conditions of tissue injury and stress. Hypothesis: We hypothesized that serum GDF-15 can predict obstructive CAD and need of revascularization among acutely admitted chest pain patients. Further, we assessed whether the combination of GDF-15 and coronary artery calcium (CAC) scoring could identify a subgroup with low risk of obstructive CAD, in whom a full coronary CT angiography (CCTA) could be avoided. Methods: GDF-15 was measured, using the assay on Cobas e801 (Roche Diagnostics), in 537 patients with chest pain and high-sensitivity cardiac troponin T concentrations ≤99th percentile. All participants underwent CAC scoring and CCTA. Obstructive CAD was defined as &gt;50% lumen diameter narrowing. Associations of GDF-15 with obstructive CAD and 30-days revascularization were calculated by multivariable logistic regression adjusting for age, sex, smoking, hypertension, HbA1c, LDL-cholesterol, GFR and prior AMI. We also evaluated whether GDF-15 could improve sensitivity and negative predictive value (NPV) of CAC=0 for ruling out the presence of obstructive CAD. Results: The median (25th-75th percentile) age was 56 (49-65) years, 217 (40.4%) of the patients were women, 83 (15.5%) had obstructive CAD, and 49 (9.1%) had revascularization within 30 days. After multivariable adjustment, elevated GDF-15 (≥1200pg/mL) predicted obstructive CAD at baseline with OR (95%CI) of 2.23 (1.14-4.36), p=0.02. The OR (95%CI) for 30-days revascularization was 2.33 (1.08-5.03), p=0.03. For CAC=0, we observed a sensitivity (95%CI) and NPV (95%CI) of 94.0% (86.5%-98.0%) and 98.0% (95.3%-99.3%) in ruling out obstructive CAD. For patients having both CAC=0 and GDF-15 levels below median (&lt;730pg/mL), sensitivity (95%CI) and NPV (95%CI) for obstructive CAD were 97.6% (91.6%-99.7%) and 98.7 (95.2%-99.8%), respectively. Conclusions: Elevated serum GDF-15 predicts obstructive CAD and 30 days revascularization among patients with chest pain, but without AMI. The combination of low GDF-15 levels and CAC=0 appears promising for the identification of low-risk patients, who can possibly be discharged without a full CCTA.

Shexiang Baoxin Pill treats acute myocardial infarction by promoting angiogenesis via GDF15-TRPV4 signaling

Angiogenesis has been considered a pivotal strategy for treating ischemic heart disease. One possible approach, the Shexiang Baoxin Pill (MUSKARDIA), has been noted to promote angiogenesis, but its underlying mechanism is still largely unknown. We aimed to determine the effects of MUSKARDIA on acute myocardial infarction (AMI), as well as the underlying mechanistic bases. AMI was induced in rats, using left anterior descending coronary arterial occlusion, and either 6 (low) or 12 (high-dose) mg/kg/day of MUSKARDIA was administered for 56 days. We found that MUSKARDIA improved cardiac function and counteracted against adverse remodeling among AMI rats, which most likely is due to it promoting angiogenesis. Transcriptome analysis by RNA-sequencing found that MUSKARDIA up-regulated cardiac pro-angiogenic genes, particularly growth differentiation factor 15 (GDF15), which was confirmed by RT-qPCR. This up-regulation was also correlated with elevated serum GDF15 levels. In vitro analyses with human umbilical vein endothelial cells found that increased GDF15, stimulated by MUSKARDIA, resulted in enhanced cell migration, proliferation, and tubular formation, all of which were reversed after GDF15 knockdown using a lentiviral vector. Gene Ontology, as well as Kyoto Genes and Genomes enrichment analyses identified calcium signaling pathway as a major contributor to these outcomes, which was verified by Western blot and Cal-590 AM loading showing that transient receptor potential cation channel subfamily V member 4 protein (TRPV4) and intracellular Ca2+ levels increased in accordance with MUSKARDIA-induced GDF15 up-regulation, and decreased with GDF15 knock-down. Therefore, MUSKARDIA may exert its cardioprotective effects via stimulating the GDF15/TRPV4/calcium signaling/angiogenesis axis.

Growth differentiation factor‑15 in patients with gestational diabetes mellitus and its relationship with microalbuminuria.

Gestational diabetes mellitus (GDM) is a common pregnancy-related complication and growth differentiation factor-15 (GDF-15) is involved in a number of diseases; therefore, the aim of the present study was to investigate the level and clinical significance of serum GDF-15 levels in patients with GDM. A total of 237 pregnant women at 20-24 weeks of gestation were selected and assigned to a normal pregnancy group (70 patients) and a GDM group (167 patients) according to the presence or absence of GDM. The general clinical data of the two groups were collected. Fasting plasma glucose, 1-h plasma glucose, 2-h plasma glucose, glycated hemoglobin, fasting insulin, 24-h urinary albumin and serum GDF-15 levels were measured. The results showed that the body mass index (BMI) of the GDM group was higher than that of the normal pregnancy group. Fasting plasma glucose, 1-h plasma glucose, 2-h plasma glucose, fasting insulin, glycated hemoglobin and GDF-15 levels and the positive rate of microalbuminuria were significantly higher in the GDM group compared with the normal pregnancy group. GDF-15 levels were positively correlated with BMI, fasting plasma glucose, glycated hemoglobin, homeostasis model assessment-insulin resistance and fasting insulin levels. Logistic regression analysis suggested that elevated GDF-15 levels are an independent risk factor for microalbuminuria. In conclusion, serum GDF-15 levels are strongly associated with GDM and elevated GDF-15 levels are an independent risk factor for microalbuminuria. Serum GDF-15 may act as a novel biomarker for predicting microalbuminuria in GDM patients.

GDF15 Promotes the Osteogenic Cell Fate of Periodontal Ligament Fibroblasts, thus Affecting Their Mechanobiological Response.

Periodontal ligament fibroblasts (PdLFs) exert important functions in oral tissue and bone remodeling following mechanical forces, which are specifically applied during orthodontic tooth movement (OTM). Located between the teeth and the alveolar bone, mechanical stress activates the mechanomodulatory functions of PdLFs including regulating local inflammation and activating further bone-remodeling cells. Previous studies suggested growth differentiation factor 15 (GDF15) as an important pro-inflammatory regulator during the PdLF mechanoresponse. GDF15 exerts its effects through both intracrine signaling and receptor binding, possibly even in an autocrine manner. The extent to which PdLFs are susceptible to extracellular GDF15 has not yet been investigated. Thus, our study aims to examine the influence of GDF15 exposure on the cellular properties of PdLFs and their mechanoresponse, which seems particularly relevant regarding disease- and aging-associated elevated GDF15 serum levels. Therefore, in addition to investigating potential GDF15 receptors, we analyzed its impact on the proliferation, survival, senescence, and differentiation of human PdLFs, demonstrating a pro-osteogenic effect upon long-term stimulation. Furthermore, we observed altered force-related inflammation and impaired osteoclast differentiation. Overall, our data suggest a major impact of extracellular GDF15 on PdLF differentiation and their mechanoresponse.

BASELINE CARDIAC BIOMARKER ANALYSIS FROM THE BASEL POSTPARTUM HYPERTENSION REGISTRY

Objective: Postpartum hypertension (PPHT) is defined by elevated blood pressure measurements after birth of more than 140 mmHg systolic and more than 90 mmHg diastolic, that persist or develop directly after pregnancy and is associated with adverse cardiovascular and renal outcome. Aim of the current analysis was the evaluation of different prognostic cardiac and stress related biomarkers like cardiac troponin T (cTnT), N-terminal pro-Brain Natriuretic Peptide (NT-proBNP) and growth differentiation factor 15 (GDF-15) in the setting of PPHT. Design and method: Enrollment for the prospective observational Basel Postpartum Hypertension Registry began in June 2020 at the University Hospital Basel. Women with preexisting hypertension, hypertensive disorders of pregnancy (HDP), and de novo postpartum hypertension were enrolled and followed up in structured management program. Clinical history and lab values were collected out of the electronic health records. Additional blood samples were stored for further evaluation. The present analysis contains biomarker analysis of a subset of 58 out of 288 patients using blood samples taken within one week of giving birth. Serum samples were analyzed for detectable levels of cTnT, NT-proBNP and GDF-15 at the department for Laboratory Medicine at University Hospital Basel using electrochemiluminescence immunoassay Elecsys on the Cobas e 801 platform (Roche Diagnostics, Rotkreuz, Switzerland). Results: Mean age of the patients from whom we measured biomarkers at baseline was 34±4.7. Mean troponin was 8.5 ng/l ±2.2 with normal cuttoffs for this age group being 14ng/l and sex specific cutoffs at 9ng/l. NT-proBNP was 229.86ng/l ±80.4, with 125ng/l being the normal cut off in an acute disease setting. Mean GDF-15 was 1895.8ng/l ±323.5 with correlating normal values in healthy populations in the same age range being 564 ± 223 ng/l. Conclusions: This first biomarker analysis shows a trend of elevated NT-proBNP and GDF-15 which are associated with cardiovascular disease or stress. Cardiac troponin T was not elevated in most of the patients, but in a subset of 13 patients. Further analysis and long term outcome correlations remains to be established and may be part of the follow-up analyses of the Basel PPHT cohort.

Phase 2 study to assess the efficacy, safety, and tolerability of the GDF-15 inhibitor ponsegromab in patients with cancer cachexia.

TPS12147 Background: Cancer cachexia is a multifactorial metabolic syndrome of wasting characterized by anorexia, unintended weight loss, and decreased skeletal muscle mass, leading to progressive functional impairment, fatigue, diminished quality of life, poor response to anticancer therapy, and reduced survival. One of the biomarkers associated with cancer cachexia is cytokine growth differentiation factor 15 (GDF-15), which is secreted by tumor cells. Preliminary phase 1 data suggest that suppression of GDF-15 may lead to improvement in cachexia-related symptom burden. Ponsegromab is a potent and selective humanized monoclonal antibody that inhibits GDF-15-mediated signaling. The primary objective of this study (NCT05546476) is to assess the effect of ponsegromab on body weight in patients with cancer, cachexia, and elevated circulating GDF-15 concentrations. Secondary objectives include assessing physical activity, gait, anorexia/appetite, nausea and vomiting, fatigue, and safety. Exploratory objectives include evaluating pharmacokinetics, pharmacodynamics, and immunogenicity. Methods: This phase 2 study will enroll approximately 168 adults with non–small cell lung, pancreatic, or colorectal cancers who have cachexia and elevated GDF-15 concentrations. The study will be conducted in 2 parts. The initial 12-week treatment period will be a randomized, double-blind, placebo-controlled study wherein participants who meet eligibility criteria will be randomized 1:1:1:1 to one of 3 dose groups of ponsegromab (administered subcutaneously [SC] every 4 weeks [Q4W]) or placebo. The double-blind period will be followed by optional open-label treatment (OLT) with ponsegromab Q4W SC for up to 1 year. Upon completion of the optional OLT period, there will be a follow-up visit at Week 72. Participants who do not proceed with the optional OLT period will complete the Week 12 visit and a follow-up visit at Week 16. The primary endpoint is the mean change from baseline in body weight at Week 12. A mixed model for repeated measures followed by a Bayesian Emax model will be used for the primary analysis. Secondary endpoints include physical activity and gait measured by remote digital sensors; patient-reported appetite-related symptoms assessed by Functional Assessment of Anorexia-Cachexia Therapy scores; anorexia/appetite, nausea, vomiting, and fatigue evaluated according to questions from the Cancer-related Cachexia Symptom Diary; and incidence of adverse events, safety laboratory tests, vital signs, and electrocardiogram abnormalities. © 2023 American Association for Cancer Research®. Reused with permission. Clinical trial information: NCT05546476 .

Screening study of anti-emetics to improve GDF15-induced malaise and anorexia: Implications for emesis control

Considerable preclinical and clinical attention has focused on the food intake and body weight suppressive effects of growth differentiation factor 15 (GDF15) and its elevated blood levels as a consequence of disease states and disease treatment therapeutics. We have previously reported that exogenous administration of GDF15 induces anorexia through nausea and emesis in multiple species. Importantly, GDF15 signaling as a meditator of chemotherapy-induced anorexia and emesis has recently been demonstrated in both murine and nonhuman primate models. The mechanism, however, by which GDF15 induces malaise and the utility of existing therapeutic targets to counteract its effects remain largely unknown. Using a dose of GDF15 that mimics stimulated levels following chemotherapy administration and reliably induces malaise, we sought to screen anti-emetics that represent distinct pharmacotherapeutic classes hypothesized to reduce GDF15-induced effects in rats. Strikingly, our results showed that none of the tested compounds were effective at preventing GDF15-induced malaise. These results illustrate the complexity of GDF15 signaling mechanism and may have important implications for medical conditions characterized by elevated GDF15 levels and incomplete symptom control, such as chemotherapy-induced nausea and vomiting.

Abstract CT108: First-in-patient study of the GDF-15 inhibitor ponsegromab in patients with cancer and cachexia: Safety, tolerability, and exploratory measures of efficacy

Abstract Background: Cachexia is common in patients with advanced cancer and has been associated with elevated serum growth/differentiation factor 15 (GDF-15) concentrations. This first-in-patient, phase 1b, study assessed the use of ponsegromab, a monoclonal antibody against GDF-15, in participants with advanced cancer and cachexia. Methods: Adult participants (n = 10) with cachexia, advanced cancer (non-small cell lung, colorectal, or pancreatic), and elevated serum concentrations of GDF-15 received open-label subcutaneous ponsegromab every three weeks (Q3W) for 12 weeks in addition to standard of care anti-cancer treatment. Study endpoints included assessment of ponsegromab safety, tolerability, and pharmacokinetics. Serum GDF-15 concentrations and exploratory measures of efficacy were also assessed. Results: No treatment-related adverse events or injection site reactions were reported. No adverse trends in clinical laboratory tests, vital signs, or electrocardiogram parameters attributable to ponsegromab dosing were evident. Ninety-two adverse events deemed unrelated to treatment were reported; most were mild (Grade 1 = 58.7%) or moderate (Grade 2 = 28.3%) in severity. All participants were negative for anti-drug antibodies at baseline (n = 10) and after receiving 5 doses (Q3W) of ponsegromab (n = 9). Mean unbound ponsegromab Ctrough ranged from 4.041-4383 ng/mL between Days 22-106. An elevated GDF-15 concentration was required for inclusion in the study. Following initiation of study treatment, median unbound GDF-15 concentration was reduced to below the lower limit of quantification (0.0424 ng/mL) on day 1 and remained suppressed until week 15 (3 weeks after final dose). Increases in body weight were observed at all time points during the treatment (weeks 3, 6, 9, and 12) and follow-up (weeks 15, 18, and 24) periods. The mean (SD) body weight at baseline was 70.49 (16.97) kg. An LS mean (SE) increase of 4.63 kg (1.98) was observed at week 12 (end of treatment); representing an increase of approximately 6.5% relative to baseline. Improvements in actigraphy-based assessments of physical activity and in quality of life, including appetite, as assessed by Functional Assessment of Anorexia-Cachexia Therapy (FAACT) total and subscale scores, were also observed during the course of ponsegromab treatment. Conclusions: In participants with advanced cancer, cachexia, and elevated baseline GDF-15, ponsegromab was well tolerated and suppressed serum GDF-15 concentrations to below the median concentration seen in healthy subjects. Preliminary evidence of efficacy, including a mean observed weight gain of approximately 6.5% at 12 weeks, supports continued development of ponsegromab for the treatment of cancer cachexia. Funded by Pfizer. ClinicalTrials.gov: NCT04299048 Citation Format: Jeffrey Crawford, Roberto A. Calle, Susie M. Collins, Yan Weng, Shannon L. Lubaczewski, Clare Buckeridge, Ellen Q. Wang, Magdalena A. Harrington, Anil Tarachandani, Michelle I. Rossulek, James H. Revkin. First-in-patient study of the GDF-15 inhibitor ponsegromab in patients with cancer and cachexia: Safety, tolerability, and exploratory measures of efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT108.

Abstract CT054: Phase 2 study to assess the efficacy, safety, and tolerability of the GDF-15 inhibitor ponsegromab in patients with cancer cachexia

Abstract Background: Cancer cachexia is a multifactorial metabolic syndrome of wasting characterized by anorexia, unintended weight loss, and decreased skeletal muscle mass, leading to progressive functional impairment, fatigue, diminished quality of life, poor response to anticancer therapy, and reduced survival. One of the biomarkers associated with cancer cachexia is cytokine growth differentiation factor 15 (GDF-15), which is secreted by tumor cells. Preliminary phase 1 data suggest that suppression of GDF-15 may lead to improvement in cachexia-related symptom burden. Ponsegromab is a potent and selective humanized monoclonal antibody that inhibits GDF-15-mediated signaling. The primary objective of this study (NCT05546476) is to assess the effect of ponsegromab on body weight in patients with cancer, cachexia, and elevated circulating GDF-15 concentrations. Secondary objectives include assessing physical activity, gait, anorexia/appetite, nausea and vomiting, fatigue, and safety. Exploratory objectives include evaluating pharmacokinetics, pharmacodynamics, and immunogenicity. Trial design: This phase 2 study will enroll approximately 168 adults with non-small cell lung, pancreatic, or colorectal cancers who have cachexia and elevated GDF-15 concentrations. The study will be conducted in 2 parts. The initial 12-week treatment period will be a randomized, double-blind, placebo-controlled study wherein participants who meet eligibility criteria will be randomized 1:1:1:1 to one of 3 dose groups of ponsegromab (administered subcutaneously [SC] every 4 weeks [Q4W]) or placebo. The double-blind period will be followed by optional open-label treatment (OLT) with ponsegromab Q4W SC for up to 1 year. Upon completion of the optional OLT period, there will be a follow-up visit at Week 72. Participants who do not proceed with the optional OLT period will complete the Week 12 visit and a follow-up visit at Week 16. The primary endpoint is the mean change from baseline in body weight at Week 12. A mixed model for repeated measures followed by a Bayesian Emax model will be used for the primary analysis. Secondary endpoints include physical activity and gait measured by remote digital sensors; patient-reported appetite-related symptoms assessed by Functional Assessment of Anorexia-Cachexia Therapy scores; anorexia/appetite, nausea, vomiting, and fatigue evaluated according to questions from the Cancer-related Cachexia Symptom Diary; and incidence of adverse events, safety laboratory tests, vital signs, and electrocardiogram abnormalities. ClinicalTrials.gov identifier: NCT05546476 Citation Format: Jeffrey Crawford, Shannon Lubaczewski, Anil Tarachandani, Magdalena A. Harrington, Yan Weng, Ruolun Qiu, Susie M. Collins, Michelle I. Rossulek, James H. Revkin. Phase 2 study to assess the efficacy, safety, and tolerability of the GDF-15 inhibitor ponsegromab in patients with cancer cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT054.

A Nrf2-OSGIN1&2-HSP70 axis mediates cigarette smoke-induced endothelial detachment: implications for plaque erosion.

Endothelial erosion of plaques is responsible for ∼30% of acute coronary syndromes (ACS). Smoking is a risk factor for plaque erosion, which most frequently occurs on the upstream surface of plaques where the endothelium experiences elevated shear stress. We sought to recreate these conditions in vitro to identify potential pathological mechanisms that might be of relevance to plaque erosion. Culturing human coronary artery endothelial cells (HCAECs) under elevated flow (shear stress of 7.5 Pa) and chronically exposing them to cigarette smoke extract (CSE) and tumour necrosis factor-alpha (TNFα) recapitulated a defect in HCAEC adhesion, which corresponded with augmented Nrf2-regulated gene expression. Pharmacological activation or adenoviral overexpression of Nrf2 triggered endothelial detachment, identifying Nrf2 as a mediator of endothelial detachment. Growth/Differentiation Factor-15 (GDF15) expression was elevated in this model, with protein expression elevated in the plasma of patients experiencing plaque erosion compared with plaque rupture. The expression of two Nrf2-regulated genes, OSGIN1 and OSGIN2, was increased by CSE and TNFα under elevated flow and was also elevated in the aortas of mice exposed to cigarette smoke in vivo. Knockdown of OSGIN1&2 inhibited Nrf2-induced cell detachment. Overexpression of OSGIN1&2 induced endothelial detachment and resulted in cell cycle arrest, induction of senescence, loss of focal adhesions and actin stress fibres, and disturbed proteostasis mediated in part by HSP70, restoration of which reduced HCAEC detachment. In ACS patients who smoked, blood concentrations of HSP70 were elevated in plaque erosion compared with plaque rupture. We identified a novel Nrf2-OSGIN1&2-HSP70 axis that regulates endothelial adhesion, elevated GDF15 and HSP70 as biomarkers for plaque erosion in patients who smoke, and two therapeutic targets that offer the potential for reducing the risk of plaque erosion.