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Collagen prolyl 4\u2010hydroxylases (C\u2010P4Hs) hydroxylate proline residues in the \u2010X\u2010Pro\u2010Gly\u2010 repeats of all known collagen types. Their product, 4\u2010hydroxyproline, is essential for correct folding and thermal stability of the triple\u2010helical collagen molecules in physiological body temperatures. We have previously shown that inactivation of the mouse\n                    <jats:italic>P4ha1<\/jats:italic>\n                    gene, which codes for the catalytic \u03b1 subunit of the major C\u2010P4H isoform, is embryonic lethal, whereas inactivation of the\n                    <jats:italic>P4ha2<\/jats:italic>\n                    gene produced only a minor phenotype. Instead, mice with a haploinsufficiency of the\n                    <jats:italic>P4ha1<\/jats:italic>\n                    gene combined with a homozygous deletion of the\n                    <jats:italic>P4ha2<\/jats:italic>\n                    gene present with a moderate chondrodysplasia due to transient cell death of the growth plate chondrocytes. Here, to further characterize the bone phenotype of the\n                    <jats:italic>P4ha1<\/jats:italic>\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    ;\n                    <jats:italic>P4ha2<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice, we have carried out gene expression analyses at whole\u2010tissue and single\u2010cell levels, biochemical analyses, microcomputed tomography, histomorphometric analyses, and second harmonic generation microscopy to show that C\u2010P4H \u03b1 subunit expression peaks early and that the C\u2010P4H deficiency leads to reduced collagen amount, a reduced rate of bone formation, and a loss of trabecular and cortical bone volume in the long bones. The total osteoblast number in the proximal\n                    <jats:italic>P4ha1<\/jats:italic>\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    ;\n                    <jats:italic>P4ha2<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    tibia and the C\u2010P4H activity in primary\n                    <jats:italic>P4ha1<\/jats:italic>\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    ;\n                    <jats:italic>P4ha2<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    osteoblasts were reduced, whereas the population of osteoprogenitor colony\u2010forming unit fibroblasts was increased in the\n                    <jats:italic>P4ha1<\/jats:italic>\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    ;\n                    <jats:italic>P4ha2<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    marrow. Thus, the\n                    <jats:italic>P4ha1<\/jats:italic>\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    ;\n                    <jats:italic>P4ha2<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mouse model recapitulates key aspects of a recently recognized congenital connective tissue disorder with short stature and bone dysplasia caused by biallelic variants of the human\n                    <jats:italic>P4HA1<\/jats:italic>\n                    gene. Altogether, the data demonstrate the allele dose\u2010dependent importance of the C\u2010P4Hs to the developing organism and a threshold effect of C\u2010P4H activity in the proper production of bone matrix. \u00a9 2022 The Authors.\n                    <jats:italic>JBMR Plus<\/jats:italic>\n                    published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.\n                  <\/jats:p>","DOI":"10.1002\/jbm4.10630","type":"journal-article","created":{"date-parts":[[2022,4,14]],"date-time":"2022-04-14T06:48:57Z","timestamp":1649918937000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Reduced Bone Mass in Collagen Prolyl 4\u2010Hydroxylase\n                    <i>P4ha1<\/i>\n                    <sup>+\/\u2212<\/sup>\n                    ;\n                    <i>P4ha2<\/i>\n                    <sup>\u2212\/\u2212<\/sup>\n                    Compound Mutant 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