An Exploratory Study of Vitamin D and Matrix Metalloproteinase and Their Regulators in Polyendocrine Metabolic...

Objective: Vitamin D has been reported to act as a tissue-protective regulator by suppressing Matrix Metalloproteinases (MMPs) and upregulating Tissue Inhibitors of Metalloproteinases (TIMPs), though changes may be body mass index (BMI)-dependent; however, the relationship between vitamin D metabolism and matrix remodeling pathways in Polyendocrine Metabolic Ovarian Syndrome (PMOS) remains poorly understood. Methods: In women with PMOS (n = 28) and controls (n = 28), 12 MMPs and 3 TIMPs were determined by Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement and correlated to 25-hydroxyvitamin D₃ (25(OH)D₃) and its metabolites (active 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) and 24,25-dihydroxyvitamin D₃ (24,25(OH)₂D₃)) measured by gold standard isotope-dilution liquid chromatography tandem mass spectrometry. Results: Insulin resistance and systemic inflammation (normal C-reactive protein) were comparable between PMOS and control women, though PMOS had higher free androgen index and anti-Mullerian hormone levels. Vitamin D and its metabolites did not differ between groups. Only MMP16 was lower in PMOS than controls (549.6 ± 58.3 vs. 678.0 ± 304.1 Relative Fluorescent Units, p = 0.037) but did not pass the false discovery rate. In women with PMOS, 25(OH)D₃ and 24,25(OH)₂D₃ demonstrated significant inverse correlations with TIMP3 (r = -0.60, p = 0.005 and r = -0.58, p = 0.007, respectively). Multivariable regression confirmed independent inverse associations between TIMP3 and both 25(OH)D₃ (β = -51.1, p = 0.031) and 24,25(OH)₂D₃ (β = -858.7, p = 0.028) after adjustment for age, body mass index and Homeostatic Model Assessment-Insulin Resistance, and the association remained stable following bootstrap internal validation. Additional moderate associations were observed between vitamin D metabolites and membrane-type MMPs (MMP14, MMP16, MMP17). Conclusions: Exploratory analyses suggested potential inverse associations between vitamin D metabolites and TIMP3, together with weaker associations involving MMP14, MMP16 and MMP17, suggesting the novel hypothesis that vitamin D may influence extracellular matrix remodeling and ovarian stromal biology through regulation of TIMP3-dependent pathways independently of obesity and insulin resistance, rather than through MMPs directly.