Substantially Delayed Maturation of Growth Plate Chondrocytes in "Humanized" Mice with the H223R Mutation of Jansen's Disease.

Activating parathyroid hormone (PTH)/PTH-related Peptide (PTHrP) receptor (PTH1R) mutations causes Jansen's metaphyseal chondrodysplasia (JMC), a rare disease characterized by growth plate abnormalities, short stature, and PTH-independent hypercalcemia. Previously generated transgenic JMC mouse models, in which the human allele with the H223R mutation () is expressed in osteoblasts via type Ia1 collagen or DMP1 promoters cause excess bone mass, while expression of the mutant allele via the type IIa1 collagen promoter results in only minor growth plate changes. Thus, neither transgenic JMC model adequately recapitulates the human disease. We therefore generated "humanized" JMC mice in which the allele was expressed via the endogenous mouse promoter and, thus, in all relevant target tissues. Founders with the H223R allele typically died within 2 months without reproducing; several mosaic male founders, however, lived longer and produced F1 offspring, which were small and exhibited marked growth plate abnormalities. Serum calcium and phosphate levels of the mutant mice were not different from wild-type littermates, but serum PTH and P1NP were reduced significantly, while CTX-1 and CTX-2 were slightly increased. Histological and RNAscope analyses of the mutant tibial growth plates revealed markedly expanded zones of type II collagen-positive, proliferating/prehypertrophic chondrocytes, abundant apoptotic cells in the growth plate center and a progressive reduction of type X collagen-positive hypertrophic chondrocytes and primary spongiosa. The "humanized" mice are likely to provide a more suitable model for defining the JMC phenotype and for assessing potential treatment options for this debilitating disease of skeletal development and mineral ion homeostasis. © 2023 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.