Daily Endocrinology Research Analysis
Mechanistic studies reveal how redox metabolism safeguards skeletal and vascular homeostasis: the pentose phosphate pathway (PPP) maintains proteostasis and prevents ferroptosis in chondrocytes, while endothelial IGFBP6 restrains inflammation and atherosclerosis via MVP–JNK/NF-κB signaling. Clinically, a multicenter U.S. analysis in transgender and gender-diverse adults refines injectable estradiol dosing, showing guideline-range levels at lower weekly doses and emphasizing timing of blood draws
Summary
Mechanistic studies reveal how redox metabolism safeguards skeletal and vascular homeostasis: the pentose phosphate pathway (PPP) maintains proteostasis and prevents ferroptosis in chondrocytes, while endothelial IGFBP6 restrains inflammation and atherosclerosis via MVP–JNK/NF-κB signaling. Clinically, a multicenter U.S. analysis in transgender and gender-diverse adults refines injectable estradiol dosing, showing guideline-range levels at lower weekly doses and emphasizing timing of blood draws.
Research Themes
- Redox metabolism and ferroptosis control in cartilage biology
- Endothelial anti-inflammatory pathways in atherosclerosis
- Optimization of gender-affirming hormone therapy dosing and monitoring
Selected Articles
1. The pentose phosphate pathway controls oxidative protein folding and prevents ferroptosis in chondrocytes.
Using chondrocyte-specific G6PD loss, the study shows that PPP-derived NADPH is indispensable to buffer ROS generated during oxidative protein folding. NADPH depletion compromises glutathione recycling, triggers unfolded protein response, induces ferroptosis, and culminates in chondrodysplasia, establishing PPP as a redox gatekeeper of proteostasis in hypoxic cartilage.
Impact: Reveals a previously underappreciated role of PPP in coupling oxidative protein folding to redox homeostasis and ferroptosis avoidance in chondrocytes, linking metabolism directly to skeletal development and repair.
Clinical Implications: Suggests that enhancing PPP flux or NADPH availability, or targeting ferroptosis pathways, could be explored to improve cartilage resilience in growth disorders and fracture repair.
Key Findings
- Chondrocyte G6PD loss reduces NADPH, impairing glutathione recycling and protection against ROS generated during oxidative protein folding.
- Proteostasis is disturbed with activation of the unfolded protein response and increased protein degradation.
- Oxidative stress triggers ferroptosis and matrix alterations, producing a chondrodysplasia phenotype, establishing PPP as essential for endochondral ossification.
Methodological Strengths
- Use of cell type–specific genetic perturbation (G6PD loss) to dissect pathway function in vivo.
- Integration of redox biology, proteostasis readouts, and phenotypic skeletal outcomes to establish causality.
Limitations
- Preclinical models may not fully capture human cartilage pathophysiology.
- Specific therapeutic interventions modulating PPP/ferroptosis were not tested in disease models.
Future Directions: Evaluate pharmacologic PPP activation or ferroptosis inhibitors in models of growth plate pathology and fracture repair; examine PPP–proteostasis coupling in human cartilage and chondrodysplasia.
Bone lengthening and fracture repair depend on the anabolic properties of chondrocytes that function in an avascular milieu. The limited supply of oxygen and nutrients calls into question how biosynthesis and redox homeostasis are guaranteed. Here we show that glucose metabolism by the pentose phosphate pathway (PPP) is essential for endochondral ossification. Loss of glucose-6-phosphate dehydrogenase in chondrocytes does not affect cell proliferation because reversal of the non-oxidative PPP produces ribose-5-phosphate. However, the decreased NADPH production reduces glutathione recycling, resulting in decreased protection against the reactive oxygen species (ROS) produced during oxidative protein folding. The disturbed proteostasis activates the unfolded protein response and protein degradation. Moreover, the oxidative stress induces ferroptosis, which, together with altered matrix properties, results in a chondrodysplasia phenotype. Collectively, these data show that in hypoxia, the PPP is crucial to produce reducing power that confines ROS generated by oxidative protein folding and thereby controls proteostasis and prevents ferroptosis.
2. Endothelial IGFBP6 suppresses vascular inflammation and atherosclerosis.
IGFBP6 is downregulated in human atherosclerosis and acts within endothelial cells to blunt inflammation by inhibiting MVP–JNK/NF-κB signaling. Loss of IGFBP6 exacerbates, while endothelial overexpression protects against, diet- and disturbed-flow–induced atherosclerosis, nominating IGFBP6 as a therapeutic target.
Impact: Identifies an endothelial-intrinsic, targetable brake on vascular inflammation with convergent human, mechanistic, and in vivo evidence.
Clinical Implications: IGFBP6 may serve as a biomarker for vascular risk and a candidate for endothelium-targeted therapies to reduce inflammation and atherosclerosis.
Key Findings
- IGFBP6 levels are decreased in human atherosclerotic arteries and serum.
- Endothelial IGFBP6 knockdown increases inflammatory gene expression and monocyte adhesion; overexpression reverses disturbed flow/TNF-induced inflammation.
- IGFBP6 signals via the MVP–JNK/NF-κB axis; IGFBP6 deficiency aggravates, while endothelial overexpression protects against, atherosclerosis in mice.
Methodological Strengths
- Concordant human tissue/serum observations with mechanistic in vitro perturbations in endothelial cells.
- Bidirectional in vivo genetics (loss- and gain-of-function) establishing causal links to atherosclerosis.
Limitations
- Translational relevance to human therapeutic modulation of IGFBP6 requires clinical studies.
- Potential off-target or systemic effects of modulating IGFBP6 were not fully characterized.
Future Directions: Develop endothelium-targeted strategies to augment IGFBP6, validate MVP–JNK/NF-κB modulation in human endothelium ex vivo, and test biomarker utility in prospective cohorts.
Beyond dyslipidemia, inflammation contributes to the development of atherosclerosis. However, intrinsic factors that counteract vascular inflammation and atherosclerosis remain scarce. Here we identify insulin-like growth factor binding protein 6 (IGFBP6) as a homeostasis-associated molecule that restrains endothelial inflammation and atherosclerosis. IGFBP6 levels are significantly reduced in human atherosclerotic arteries and patient serum. Reduction of IGFBP6 in human endothelial cells by siRNA increases inflammatory molecule expression and monocyte adhesion. Conversely, pro-inflammatory effects mediated by disturbed flow (DF) and tumor necrosis factor (TNF) are reversed by IGFBP6 overexpression. Mechanistic investigations further reveal that IGFBP6 executes anti-inflammatory effects directly through the major vault protein (MVP)-c-Jun N-terminal kinase (JNK)/nuclear factor kappa B (NF-κB) signaling axis. Finally, IGFBP6-deficient mice show aggravated diet- and DF-induced atherosclerosis, whereas endothelial-cell-specific IGFBP6-overexpressing mice protect against atherosclerosis. Based on these findings, we propose that reduction of endothelial IGFBP6 is a predisposing factor in vascular inflammation and atherosclerosis, which can be therapeutically targeted.
3. Injectable Estradiol Use in Transgender and Gender-Diverse Individuals throughout the United States.
In a multicenter retrospective analysis of 562 TGD adults on stable weekly injectable estradiol, guideline-range estradiol was achieved at a median 4 mg per week, while many patients exhibited supraphysiologic levels. Estradiol concentrations were strongly influenced by dose and time since last injection, with no meaningful differences between IM vs SC routes or between valerate vs cypionate.
Impact: Provides real-world, multicenter dosing data that refine injectable estradiol regimens and laboratory interpretation, addressing a major gap in gender-affirming care.
Clinical Implications: Consider starting and maintenance doses lower than prior practices for weekly injections; interpret serum estradiol in the context of time since last dose; route (IM vs SC) and ester selection (EV vs EC) may be chosen based on patient preference and availability.
Key Findings
- Among weekly injectors who reached guideline-recommended estradiol, the median effective dose was 4 mg (IQR 3–5 mg).
- Most patients had supraphysiologic estradiol (>200 pg/mL), and estradiol levels were significantly associated with dose and timing in the injection cycle.
- No significant dosing or concentration differences were observed between intramuscular vs subcutaneous routes or between estradiol valerate vs cypionate.
Methodological Strengths
- Large multicenter cohort with confirmed timing of blood draw relative to last injection.
- Use of weighted linear mixed models to assess covariate relationships with estradiol concentrations.
Limitations
- Retrospective cross-sectional design limits causal inference and may be subject to selection bias.
- Lack of standardized sampling across the dosing interval and potential unmeasured confounding (e.g., injection technique, adherence).
Future Directions: Prospective dosing trials to define optimal dose–frequency strategies, standardized pharmacokinetic sampling to inform target ranges, and outcomes linking dosing to safety and feminization metrics.
CONTEXT: Guidelines for use of injectable estradiol esters (valerate [EV] and cypionate [EC]) among transgender and gender-diverse (TGD) individuals designated male at birth vary considerably, with many providers noting supraphysiologic serum estradiol concentrations based on current dosing recommendations. OBJECTIVES: This work aimed to 1. determine the dose of injectable estradiol (subcutaneous [SC] and intramuscular [IM]) needed to reach guideline-recommended estradiol concentrations for TGD adults using EC/EV; 2. describe the relationship between estradiol concentration relative to timing/dose of last estradiol injection and other covariates; and 3. determine dosing differences between IM/SC EV/EC. METHODS: A cross-sectional retrospective study was conducted across 6 US medical centers including TGD adults on same-dose injectable estradiol for more than 75 days, with confirmed timing of estradiol concentration relative to last injection, from January 1, 2019 to December 31, 2023. Descriptive statistics were used to describe patient characteristics and weighted linear mixed models to evaluate relationship between various covariates and estradiol concentration. RESULTS: Data from 562 patients were included. Among those injecting every 7 days who reached the guideline-recommended estradiol concentration (n = 131, 27.5%), the median estradiol dose was 4.0 mg (interquartile range, 3.0-5.0 mg). Among all patients, the majority reached supraphysiologic estradiol concentrations (>200 pg/mL [>734 pmol/L]) while dose and timing in the injection cycle were significant covariates for the estradiol concentration. There were no significant dosing differences between IM/SC EV/EC. CONCLUSION: Injectable estradiol esters effectively reach guideline-recommended estradiol concentrations but at lower doses than previously recommended. Estradiol concentrations are best interpreted relative to timing of last injection. Route of administration and type of ester do not significantly affect estradiol concentrations.