Abstract
Keratoconus (KC) is a corneal thinning disease with an onset commonly immediately post-puberty and stabilization by 40 to 50 years of age. The role of hormones in regulating corneal tissue structure in homeostatic and pathological conditions is unknown. Our group recently linked altered hormone levels to KC. Our current study sought to investigate and delineate the effects of exogenous hormones, such as androgen, luteotropin, and estrogen, on corneal stroma bioenergetics. We utilized our established 3D in vitro model to characterize the effects of DHEA, prolactin, 17β-estradiol on insulin-growth factor-1 and -2 (IGF-1, -2) signaling and metabolic function in primary corneal fibroblasts from healthy controls (HCFs) and KC patients (HKCs). Our data showed that exogenous DHEA significantly downregulated IGF-1 and its receptor in both HCFs and HKCs with HKCs showing consistently lower basal pentose phosphate flux. Prolactin caused no significant change in IGF-1 levels and an increase in IGF-2 in HKCs correlating with an increase in ATP and NADH levels. 17β-estradiol led to a significant upregulation in pentose phosphate flux and glycolytic intermediates in HCFs. Our results identified hormone-specific responses regulated in HKCs compared to HCFs revealing a novel role for hormones on bioenergetics in KC.
Highlights
Sex hormones play a functional role in regulating growth and reproduction, systemic metabolism, and cellular differentiation and functionality[1,2,3]
In order to determine the effects of DHEA on the major pathways involved in glucose metabolism, we evaluated metabolite flux in glycolysis, tricarboxylic acid cycle (TCA), and the pentose phosphate pathway (PPP)
It is still unclear what role bioenergetics play in regulating corneal keratocyte function and how alterations may contribute to cellular responses during wounding or pathologically extracellular matrix (ECM) thinning as occurs in KC
Summary
Sex hormones play a functional role in regulating growth and reproduction, systemic metabolism, and cellular differentiation and functionality[1,2,3]. Estriol, 17β-estradiol (E2) and estrone, are produced by the ovaries in females and in small amounts by the prostate in males Many of these hormones are known to regulate IGF-1 signaling directly during development and in pathological states, such as cancer[13,14,15,16]. Localized IGF-1 production is suggested to play a fundamental role in regulating postnatal tissue growth compared to systemic flux[21]. Increased corneal thickness has been identified in some acromegaly patients suggesting that overproduction of IGF-1 promoted by human growth hormone may promote stromal thickening within the eye as well[24,25]. Our data revealed a novel mechanism of action of hormones in regulating IGF-1 expression and bioenergetics in corneal fibroblasts providing insight into possible causation and progression of corneal thinning in KC
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