A mouse model of Jansen's metaphyseal chondrodysplasia for investigating disease mechanisms and candidate therapeutics

• 成果类型: Article
• 署名作者: Hoeppner, Jakob; Firat, Damla; Parvez-Khan, Mohd; Reyes, Monica; Hanna, Patrick; Yadav, Prem Swaroop; Dean, Thomas; Ramos-Torres, Karla M.; Brugarolas, Pedro; Collins, Michael T.; Wein, Marc N.; Liu, Shi; Gellman, Samuel H.; Schipani, Ernestina; Kronenberg, Henry M.; Gardella, Thomas J.; Jueppner, Harald
• 署名单位: Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; University of Duisburg Essen; University of Pennsylvania; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; National Institutes of Health (NIH) - USA; NIH National Institute of Dental & Craniofacial Research (NIDCR); University of Wisconsin System; University of Wisconsin Madison; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; National University of Singapore
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10113
• DOI: 10.1073/pnas.2500176122
• 发表日期: 2025-06-10
• 关键词: hormone-related peptide; controls chondrocyte hypertrophy; parathyroid-hormone; pth/pthrp receptor; targeted expression; bone-development; inverse agonism; indian hedgehog; pth; protein

摘要

Jansen's metaphyseal chondrodysplasia (JMC) is a rare disorder caused by activating mutations in the parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor (PTH1R). Patients exhibit short stature, dysmorphic bones, and severe growth plate abnormalities, as well as hypercalcemia, hypercalciuria, hypophosphatemia, and reduced plasma PTH levels. Humanized PTH1R (hPTH1R) mice expressing the H223R-hPTH1R JMC mutation die early without breeding. We therefore generated and characterized a stable mouse line expressing the T410R-hPTH1R allele, which confers a milder disease phenotype in patients. Mutant mice show near-normal longevity and reproductive capacity yet exhibit a profound skeletal phenotype characteristic of the disease. The long bones of T410R mice are markedly misshapen and have expanded metaphyses with disarrayed chondrocyte zones in growth plates and reduced primary spongiosa. PET/CT scanning revealed diminished uptake of [18F]- sodium fluoride in the growth plate area, consistent with reduced mineralization and vascularization. Genetic ablation of Hdac4 rescued the growth plate abnormalities in T410R mice, thereby establishing the PTH1R-G alpha s-cAMP-PKA-SIK3-HDAC4/5 pathway as the main mediator of growth plate abnormalities in JMC. Serum calcium was elevated and endogenous PTH was suppressed in T410R mice, and both parameters could be normalized by acute injection of an optimized PTH inverse agonist peptide. The T410R mouse thus represents a stable animal model of JMC that recapitulates the abnormalities in skeletal development and mineral ion homeostasis which characterize this disease. The mice should help efforts to further define the cellular and molecular mechanisms underlying the JMC phenotype and to develop a potential mode of therapy.