Mechano-metabolic axis involves mitochondrial responses via BMP/Smad regulatory effect on cyclophilin D
Year: 2026
Type: article
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 osteogenic cells involves BMP/Smad-mediated downregulation of CypD and CypD-dependent mitochondrial responses. Such regulation is important for the osteoanabolic effect of mechanical stimulation. Our data also suggest that targeting CypD can be an effective strategy to prevent bone loss caused by unloading due to immobility, space flight, or tooth extraction.
Source: Bone Research
Institutions: University of Rochester Medicine, University of Rochester
Language: English
Topic: Bone Metabolism and Diseases
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,405
Awards: Training Program in Oral Science, The role of mitochondrial dysfunction in the pathogenesis of osteoarthritis, Mitochondrial metabolism and bone formation, Efferocytosis by Bone Marrow Stromal Cells and Bone Aging, Raman spectroscopic platform for transcutaneous monitoring of bone quality, Rochester Resource-Based Center for Bone, Muscle and Orthopaedic Research (ROCSTARR) (Overall Application), Energy Metabolism in Osteoblasts and Bone Health
OpenAlex ID: W7204999910