Deciphering Osteoarthritis: Insights into Reduced Chondrocyte Proliferation from PTHrP Knock-In Mouse Model Studies
Abstract
Osteoarthritis (OA) is a progressive multifactorial joint disease characterized by articular cartilage degeneration. Up to now, OA is incurable and treatment options are minimal. Parathyroid hormone-related protein (PTHrP) plays an important role in the regulation of chondrocyte development. In bone, PTHrP acts as a downstream effector, regulating the rate and size of bone formation. PTHrP consists of an N-terminus, a mid-region, a nuclear localization sequence (NLS), and a C-terminus. PTHrP mediates intracrine actions through its NLS which translocates to the nucleus to act as a transcription factor for the regulation of genes involved in growth and metabolism. We intend to explore the cellular and molecular interaction of PTHrP with other factors including signaling molecules such as insulin-like growth factor (IGF-1) whose dysregulation leads to abnormal chondrocyte function and cartilage degeneration in OA. To study the function of NLS and C-terminus of PTHrP in vivo, we generated PTHrP Δ/Δ mice (1-66) that lack the NLS and C-terminus of PTHrP. Pthrp Δ/Δ mice showed stunted growth, altered skeletal development, and most die within 5 days after birth. Previous results show a decrease in IGF-1 levels in these mice, which could lead to defects in cartilage development. Histological analysis by Alcian blue staining and immunofluorescence shows a decrease in the expression of proteoglycans and type II collagen in chondrocytes isolated from Pthrp Δ/Δ mice compared to control. Overall, the NLS and C-terminus of PTHrP are essential for normal chondrocyte function and may be protective against articular cartilage degeneration.
Keywords:
Translational Biomedical Sciences, Osteoarthritis and PTHrP
Status
Graduate
Department
Biomedical Sciences
College
Graduate College
Campus
Athens
Faculty Mentor
Rosol, Thomas
Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.
Deciphering Osteoarthritis: Insights into Reduced Chondrocyte Proliferation from PTHrP Knock-In Mouse Model Studies
Osteoarthritis (OA) is a progressive multifactorial joint disease characterized by articular cartilage degeneration. Up to now, OA is incurable and treatment options are minimal. Parathyroid hormone-related protein (PTHrP) plays an important role in the regulation of chondrocyte development. In bone, PTHrP acts as a downstream effector, regulating the rate and size of bone formation. PTHrP consists of an N-terminus, a mid-region, a nuclear localization sequence (NLS), and a C-terminus. PTHrP mediates intracrine actions through its NLS which translocates to the nucleus to act as a transcription factor for the regulation of genes involved in growth and metabolism. We intend to explore the cellular and molecular interaction of PTHrP with other factors including signaling molecules such as insulin-like growth factor (IGF-1) whose dysregulation leads to abnormal chondrocyte function and cartilage degeneration in OA. To study the function of NLS and C-terminus of PTHrP in vivo, we generated PTHrP Δ/Δ mice (1-66) that lack the NLS and C-terminus of PTHrP. Pthrp Δ/Δ mice showed stunted growth, altered skeletal development, and most die within 5 days after birth. Previous results show a decrease in IGF-1 levels in these mice, which could lead to defects in cartilage development. Histological analysis by Alcian blue staining and immunofluorescence shows a decrease in the expression of proteoglycans and type II collagen in chondrocytes isolated from Pthrp Δ/Δ mice compared to control. Overall, the NLS and C-terminus of PTHrP are essential for normal chondrocyte function and may be protective against articular cartilage degeneration.