Deletion of Tfam in Prx1-Cre expressing limb mesenchyme results in spontaneous bone fractures
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ABSTRACT:
PROVIDER: PRJNA806195 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17993600_1.fastq.gz | Fastqsanger.gz | |||
| SRR17993600_2.fastq.gz | Fastqsanger.gz | |||
| SRR17993601_1.fastq.gz | Fastqsanger.gz | |||
| SRR17993601_2.fastq.gz | Fastqsanger.gz | |||
| SRR17993602_1.fastq.gz | Fastqsanger.gz |
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Project description:Osteoblasts require substantial amounts of energy to synthesize bone matrix and coordinate the mineralization of the skeleton. This study analyzed the effect of mitochondrial dysfunction on bone formation in mouse limbs. The limb mesenchyme-specific Tfam knockout (Tfamf/f;Prx1-Cre: Tfam-cKO) mice were analyzed morphologically, and histologically and gene expression in the limb bones were assessed by in situ hybridization, quantitative real-time PCR and RNA sequencing. Moreover, we analyzed mitochondrial function of osteoblasts in Tfam-cKO mice by mitochondrial membrane potential assay and transmission electron microscopic (TEM) observations. We investigated the pathogenesis of spontaneous bone fractures by immunohistochemical analysis, TEM observations and biomechanical examination. The forelimbs in Tfam-cKO mice were significantly shortened from birth and occurred spontaneous fractures within the first week after birth, resulting in severe limb deformities. Histologically, bone hypoplasia with decrease of matrix mineralization was apparent, and the expressions of type Ⅰ collagen and osteocalcin were decreased in the osteoblasts of Tfam-cKO mice although Runx2 expression was unchanged. Decreased type Ⅰ collagen deposition and mineralization in the matrix of the limb bones in Tfam-cKO mice was associated with marked mitochondrial dysfunction. Biomechanical analysis showed significantly lower Young’s modulus and hardness due to poor apatite orientation in the bone tissue of Tfam-cKO mice. The mice with limb mesenchyme-specific Tfam deletion exhibited spontaneous limb bone fractures, resulting in severe limb deformities. Their bone fragility was caused by poor apatite orientation due to impaired osteoblasts differentiation and maturation.
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Project description:Glycolytic metabolism, once considered merely a consequence of cellular function, has emerged as a crucial regulator of cellular differentiation. Both glycolysis and oxidative phosphorylation (OXPhos) are vital for osteoblastogenesis. Osteoblasts are the cells that make bone. To deepen our understanding of OXPhos's role in bone mass accrual, we engineered a mutant mouse model deficient in Mitochondrial Transcription Factor A (TFAM) specifically in mesenchymal progenitors within the limb bud and their descendants, using the PRX1-Cre driver system. TFAM is essential for transcription of the mitochondrial genes that encode critical components of the electron transport chain, thereby governing OXPhos. Our TFAM mutant mice exhibit marked shortening of long bones, evident at birth and progressing with age, accompanied by growth plate abnormalities and bone deformities. Critically, these mice develop spontaneous fractures in long bone mid-shafts by three weeks of age, indicating significant compromise in bone integrity. Comparative analyses using MicroCT and histomorphometry reveal drastic cortical bone thinning in mutants due to severely impaired osteoid deposition and bone formation, especially in the diaphyseal periosteum. Furthermore, an increased number of osteoclasts at this site suggests that an elevated bone resorption contributes to the phenotype. Acknowledging the active role of energy metabolism in cell differentiation and function, we measured ATP production in PRX1 lineage periosteal cells. TFAM deletion led to a substantial decrease in steady-state intracellular ATP levels, highlighting a critical metabolic deficit. To rectify this metabolic defect and potentially correct the resultant phenotype, we bred TFAM mice with another mouse line expressing mutated, oxygen-independent Hypoxia Inducible Factor 1alpha (HIF1dPA) within PRX1 lineage cells (yielding TFAM/HIF1dPA mice). These double mutants did not experience spontaneous fractures, and their cortical bone thickness and the ability of periosteal cells to accumulate osteoid was fully restored. Therefore, by examining the transcriptional profile of periosteal cells, our aim is to determine whether TFAM deficiency alters their genetic landscape and if HIF1 activation can reverse these changes. Our goal is to provide new insights into the role of energy metabolism in shaping the transcriptome landscape, thereby influencing cell differentiation and activity.
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