MON-752 Nuclear PTHrP Regulates Chondrocyte Maturation And Hepatic Gene Expression

Abstract Disclosure: W.J. Hashmi: None. N. Kantake: None. I.M. Max-Harry: None. S. Zhu: None. R.E. Toribio: None. E.E. Hildreth: None. T.J. Rosol: None. Parathyroid hormone-related protein (PTHrP) plays critical roles in skeletal development and growth plate cartilage regulation. PTHrP consists of three functional regions: the N-terminus, the nuclear localization sequence (NLS), and the C-terminus. PTHrP (67-139) includes both the NLS and the C-terminus. This study investigated the effects of PTHrP (67-139) deletion in Pthrp Δ/Δ mice. Pthrp Δ/Δ mice exhibited significantly shorter growth plate cartilage, with reduced resting, proliferative, and hypertrophic zone lengths compared to controls, indicating impaired epiphyseal development. Loss of PTHrP (67-139) decreased nuclear localization of PTHrP, increased cytoplasmic PTHrP, and decreased PTHrP protein in growth plate cartilage. qPCR analysis showed increased mRNA expression of Pthrp (N-terminus) in Pthrp Δ/Δ mice. Further, Pthrp Δ/Δ mice had reduced Igf1 mRNA and protein expression of IGF1 and its receptor (IGF1R) protein expression, particularly in the proliferative zone. Pthrp Δ/Δ mice had increased Adamts5 mRNA and protein levels of ADAMTS5, suggesting enhanced extracellular matrix (ECM) degradation. Primary chondrocyte cultures from Pthrp Δ/Δ mice had significantly decreased proliferation and ECM production, shown by reduced Alcian blue staining intensity. qPCR from chondrocytes showed decreased mRNA expression of Col2a1, Adamts5, and Acan in Pthrp Δ/Δ chondrocytes. Immunofluorescence and western blot analysis confirmed reduced COL2A1 levels in Pthrp Δ/Δ mice. These findings highlighted that the absence of PTHrP (67-139) impaired chondrocyte proliferation, differentiation, and ECM production, resulting in disrupted growth plate function and skeletal abnormalities. Bulk RNA sequencing of liver tissue from Pthrp Δ/Δ mice revealed downregulation of genes involved in cell cycle and DNA replication, and upregulation of gluconeogenic pathways, suggesting systemic metabolic dysregulation. This study confirmed PTHrP (67-139)’s role in chondrocyte regulation and growth plate cartilage and liver development. Presentation: Monday, July 14, 2025