Mechano-metabolic axis involves mitochondrial responses via BMP/Smad regulatory effect on cyclophilin D
Abstract
Mechanical stimulation is fundamental for anabolism in various tissues, including bone. Importantly, mechanical stimulation has been shown to induce reprogramming of cell metabolism, likely to adjust it to increased anabolism. The signal transduction within this mechano-metabolic axis is incompletely understood. Aiming to delineate such signal transduction, we exposed osteoprogenitors to fluid shear stress (FSS) and assessed cell signaling and bioenergetics. The BMP/Smad pathway is known to be activated by mechanical stress, and we indeed detected its activation by FSS. We previously reported that BMP downregulates cyclophilin D (CypD), an opener of the mitochondrial permeability transition pore (MPTP). Downregulation of CypD/MPTP improves mitochondrial inner membrane integrity and therefore oxidative function. We found that in FSS-stimulated cells, CypD was indeed downregulated and mitochondria were activated in a BMP-dependent manner. Meanwhile, the osteogenic effect of FSS was dependent on CypD downregulation and mitochondrial responses. To confirm our in vitro results in vivo, we optimized a novel model of tooth extraction-mediated unloading of craniofacial bones in mice. Such unloading led to bone loss and upregulation of CypD in the affected bone. Osteoblast-specific deletion of CypD protected against unloading-mediated bone loss, while CypD re-expression in these mice restored bone loss. In sum, we here present new evidence that the mechano-metabolic axis in…
Read the paper
Related studies
- Multifocal clonal evolution characterized using circulating tumour DNA in a case of metastatic breast cancer
- What are the causes of late-life depression?
- Identification of SOX3 as an XX male sex reversal gene in mice and humans
- Retrospective study of concussive convulsions in elite Australian rules and rugby league footballers: phenomenology, aetiology, and outcome
- Uveal melanomas presenting during pregnancy and the investigation of oestrogen receptors in melanomas
- Metabolic and pathologic profiles of human LSS deficiency recapitulated in mice
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.