Endocrine Abstracts

We explored the role of locally produced non-pituitary tissue GH (npGH) in regulating the normal epithelial microenvironment. In contrast to declining circulating pituitary GH occurring with age, both epithelial DNA damage and aging induce local npGH expression. DNA damage, a driver of age-related pathology, accumulates consequent to local npGH- mediated defective DNA damage repair (DDR). This build-up of unrepaired DNA damage results in chromosomal instability in aged mice and also in iPSC-derived human intestinal organoids. Disrupted mutant GHR signaling in fibroblasts derived from Laron syndrome patients, as well as observed in GHRKO murine colon, both reveal high expression of tumor-suppressor p53, with less DNA damage. Similarly, injection of a selective GHR synthesis inhibitor activates DNA repair with subsequent decreased epithelial DNA damage. By contrast, pegvisomant, induces colon p53 and p21 in colon epithelium of acromegaly patients, conferring protection from DNA damage. Consistent with these finidngs, in the aged human colon, local npGH is defined as a component of the senescence-associated secretory phenotype (SASP) and elicits paracrine epithelial GHR signalling to induce local DNA damage as evidenced by co-cultured WT and GH-expressing organoids developing chromosomal instability, somatic deletions, and EMT phenotypes. These adverse microenvironmental sequelae are induced by npGH-mediated suppressed DDR proteins, EMT and migratory protein dysruptions. WIP1 phosphatase mediates GH-induced dephosphorylated ATM, leading to inactivation of DDR proteins. Wip1 inhibition mitigates GH-induced DNA damage. npGH also triggers epithelial EMT and cell motility. Enriched gene ontology and KEGG analysis of colon organoids exposed to paracrine npGH revealed distorted ECM gene expression and focal adhesion pathways. Injecting of GH-expressing fibroblasts into murine prostate glands leads to EMT and DNA damage and phenotypic features consistent with benign prostate hypertrophy. Conclusions: Paracrine npGH enables a microenvironmental landscape favoring epithelial cell transformation. Blocking local GH action may benefit healthspan and ameliorate aging-associated disorders.