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.
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.
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.