Deletion of Tfam in Prx1-Cre expressing limb mesenchyme results in spontaneous bone fractures

Hiroki Yoshioka, Shingo Komura, Norishige Kuramitsu, Atsushi Goto, Tomoka Hasegawa, Norio Amizuka, Takuya Ishimoto, Ryosuke Ozasa, Takayoshi Nakano, Yuuki Imai, Haruhiko Akiyama*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Introduction: Osteoblasts require substantial amounts of energy to synthesize the bone matrix and coordinate skeleton mineralization. This study analyzed the effects of mitochondrial dysfunction on bone formation, nano-organization of collagen and apatite, and the resultant mechanical function in mouse limbs. Materials and methods: Limb mesenchyme-specific Tfam knockout (Tfamf/f;Prx1-Cre: Tfam-cKO) mice were analyzed morphologically and histologically, and gene expressions in the limb bones were assessed by in situ hybridization, qPCR, and RNA sequencing (RNA-seq). Moreover, we analyzed the mitochondrial function of osteoblasts in Tfam-cKO mice using mitochondrial membrane potential assay and transmission electron microscopy (TEM). We investigated the pathogenesis of spontaneous bone fractures using immunohistochemical analysis, TEM, birefringence analyzer, microbeam X-ray diffractometer and nanoindentation. Results: Forelimbs in Tfam-cKO mice were significantly shortened from birth, and spontaneous fractures occurred after birth, resulting in severe limb deformities. Histological and RNA-seq analyses showed that bone hypoplasia with a decrease in matrix mineralization was apparent, and the expression of type I collagen and osteocalcin was decreased in osteoblasts of Tfam-cKO mice, although Runx2 expression was unchanged. Decreased type I collagen deposition and mineralization in the matrix of limb bones in Tfam-cKO mice were associated with marked mitochondrial dysfunction. Tfam-cKO mice bone showed a significantly lower Young’s modulus and hardness due to poor apatite orientation which is resulted from decreased osteocalcin expression. Conclusion: Mice with limb mesenchyme-specific Tfam deletions exhibited spontaneous limb bone fractures, resulting in severe limb deformities. Bone fragility was caused by poor apatite orientation owing to impaired osteoblast differentiation and maturation.

Original languageEnglish
Pages (from-to)839-852
Number of pages14
JournalJournal of Bone and Mineral Metabolism
Volume40
Issue number5
DOIs
StatePublished - 2022/09

Keywords

  • Apatite orientation
  • Mitochondrial dysfunction
  • Osteoblast differentiation
  • Spontaneous bone fracture
  • Type I collagen

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine
  • Endocrinology

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