Murine model of high bone mass osteogenesis imperfecta exhibits bone matrix hyper-mineralization, misaligned mineral crystals, and altered osteoblast differentiation

Aileen M. Barnes; M. Helen Rajpar; Joseph E. Perosky; Stéphane Blouin; Basma Khoury; MaryAnn Weis; Theresa Hefferan; Alberta Derkyi; Gali Guterman-Ram; Ghazal Hedjazi; Kiersten Campbell; Chris Stephan; David R. Eyre; Ryan K. Dale; Peter Fratzl; Kenneth M. Kozloff; Nadja Fratzl-Zelman; Joan C. Marini

doi:10.1038/s41413-026-00531-7

Bone Research ›› 2026, Vol. 14 ›› Issue (1) :67 DOI: 10.1038/s41413-026-00531-7

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Murine model of high bone mass osteogenesis imperfecta exhibits bone matrix hyper-mineralization, misaligned mineral crystals, and altered osteoblast differentiation

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¹Section on Heritable Disorders of Bone and Extracellular Matrix, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA

²Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA

³Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Med. Department Hanusch Hospital, Vienna, Austria

⁴, Vienna Bone and Growth Center, Vienna, Austria

⁵Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, WA, USA

⁶Biomaterials and Histomorphometry Core Laboratory, Mayo Clinic, Rochester, MN, USA

⁷Office of the Clinical Director, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA

⁸Bioinformatics & Scientific Programming Core, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA

⁹, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany

¹⁰Faculty of Biomedical Engineering, Technion-Israel Institute of Technology, Haifa, Israel

^a oidoc@helix.nih.gov

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Abstract

Osteogenesis imperfecta (OI), characterized by bone fragility and low bone mass, is predominantly caused by mutations in type I collagen. High bone mass OI (HBM OI) is a rare form caused by heterozygous missense mutations at the type I procollagen C-propeptide cleavage site. Knock-in HBM OI mice were generated to elucidate the effect of this mutation on cells and bone. HBM OI murine femora contain increased monomeric pro-α1(I)C-propeptide and pC-collagen; their bone collagen fibrils have a “barbed-wire” appearance. Decreased C-propeptide cleavage diminishes bone strength. HBM OI femora are extremely brittle, with thin cortices, decreased BV/TV, and fracture load. The cortical bone has increased mineral content, with thinner, more disorganized mineral particles. Increased expression of ossification genes in both murine and human HBM OI osteoblasts during in vitro differentiation and increased mineral deposition in culture indicate impaired C-propeptide processing affects cellular processes related to mineralization, rather than being a passive matrix process. Gene ontology analysis of RNA-seq data from differentiating HBM OI osteoblasts revealed top upregulated pathways for ossification, mineralization, and osteoblast differentiation (5–25×) while top-downregulated pathways involved cellular adhesion, migration, and angiogenesis (5–10×), all related to cell-matrix interactions. Moreover, the HBM matrix affects osteoblast function. WT osteoblasts plated on HBM OI decellularized matrix in vitro showed less punctate vinculin, increased peripheral actin staining, and the presence of lamellipodia, suggesting a decrease in cellular adhesion. Insights into the mechanism of HBM OI mineralization may lead to improved therapies for HBM OI and low bone mass conditions.

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Aileen M. Barnes, M. Helen Rajpar, Joseph E. Perosky, Stéphane Blouin, Basma Khoury, MaryAnn Weis, Theresa Hefferan, Alberta Derkyi, Gali Guterman-Ram, Ghazal Hedjazi, Kiersten Campbell, Chris Stephan, David R. Eyre, Ryan K. Dale, Peter Fratzl, Kenneth M. Kozloff, Nadja Fratzl-Zelman, Joan C. Marini. Murine model of high bone mass osteogenesis imperfecta exhibits bone matrix hyper-mineralization, misaligned mineral crystals, and altered osteoblast differentiation. Bone Research, 2026, 14 (1) : 67 DOI:10.1038/s41413-026-00531-7

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