Molecular Analysis of Parathyroid Hormone-related Peptide of Regenerative Gastric Mucosa

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Parathyroid hormone-related peptide (PTHrP) was first isolated from human tumor cells and was shown to be responsible for producing hypercalcemia in patients with humoral hypercalcemia of malignancy. PTHrP is the product of a gene that is also expressed in many normal tissues, and the localization of PTHrP in the stomach has been demonstrated in fetal and adult animals. Gene expression of PTH/PTHrP receptor was also demonstrated in many tissues and PTHrP elicits physiological effects through PTH/PTHrP receptor in an autocrine/paracrine fashion. Among the various physiological effects of PTHrP,smooth muscle relaxation in visceral and vascular tissues is well known. Another important physiological role of this peptide is cell proliferation and differentiation in some tissues, such as skin, cartilage, bone, and lung.The purpose of this study is to elucidate the molecular mechanisms of PTHrP on mucosal regeneration and cell cycle. Acetic acid ulcer model was used in this study and the sampling tissues were processed for immunohistochemistry, in situ hybridization, and Northern blot analysis. Expression of PTHrPmRNA was decreased in the regenerative mucosa in the early phase of ulcer healing. In contrast, PTHrP receptor mRNA was overexpressed reciprocally. Expressions of EGF and TGFbeta did not involve transcription of PTHrP in an early stage of regeneration. These results suggest that PTHrP receptor expression is important in the early events of mucosal regeneration and that PTHrP involves regulation of differentiation of the regenerative epithelium in the late phase. Moreover the sense-oligo PTHrP obviously retarded ulcer healing. Overexpression of PTHrP induces PTHrP receptor down regulation and it retards the mucosal regeneration.Further studies are planned on clarification of molecular mechanism of PTHrP on regeneration of the gastric mucosa.Finally, we acknowledge a support from this grant and a valuable contribution of our post doc fellows and staffs.