Psoriasis is a chronic, immune-mediated inflammatory skin disease induced by genetic and environmental factors, with dysfunctional contact inhibition of keratinocytes being a core pathological feature leading to hyperproliferation. Our previous gene chip screening identified a significant downregulation of PTCHD1 following treatment with recombinant human parathyroid hormone (1-34) (rhPTH(1-34)), which inhibited keratinocyte proliferation. PTCHD1 (Patched domain-containing protein 1) is a transmembrane protein that regulates intercellular communication and proliferative signaling. This study aimed to investigate whether rhPTH(1-34) restores contact inhibition and controls keratinocyte proliferation by downregulating PTCHD1 to modulate the Hippo signaling pathway. In vitro experiments showed that rhPTH(1-34) treatment significantly suppressed HaCaT cell viability, downregulated PTCHD1 mRNA and protein expression, and reduced the cell adhesion index. In a PTCHD1-overexpressing HaCaT model, enhanced cell adhesion, proliferation, and elevated IL-1β expression were observed, all of which were reversed by rhPTH(1-34). Inhibition of the Hippo pathway with Verteporfin recapitulated the contact inhibition phenotype. Mechanistically, rhPTH(1-34) downregulated PTCHD1, activated the key MST1/2-LATS1 kinase cascade, promoted phosphorylation of YAP at Ser127, and facilitated its cytoplasmic retention. In vivo, intraperitoneal injection of rhPTH(1-34) ameliorated psoriatic lesions in a mouse model, evidenced by reduced erythema, scaling, epidermal thickening, and lower inflammatory cytokine levels, without inducing fluctuations in serum calcium. In conclusion, rhPTH(1-34) restores contact inhibition and suppresses keratinocyte proliferation and inflammation by downregulating PTCHD1 to regulate the Hippo signaling pathway, demonstrating its potential as a treatment for psoriasis.
Guo et al. (2026) studied this question.