Inhibition of the mitochondrial permeability transition improves bone fracture repair

• Published in: Bone (New York, N.Y.) Vol. 137; p. 115391
• Main Authors: Shares, Brianna H., Smith, Charles O., Sheu, Tzong-Jen, Sautchuk, Rubens, Schilling, Kevin, Shum, Laura C., Paine, Ananta, Huber, Aric, Gira, Emma, Brown, Edward, Awad, Hani, Eliseev, Roman A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2020
• Subjects: Animals; Bone fracture; Cyclophilin D; Female; Fractures, Bone; Male; Mice; Mice, Knockout; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Transmembrane Permeability-Driven Necrosis; Osteoprogenitors; Peptidyl-Prolyl Isomerase F; Permeability transition; Cyclophilin D; Mitochondria; Permeability transition; Osteoprogenitors; Bone fracture
• ISSN: 8756-3282; 1873-2763
• DOI: 10.1016/j.bone.2020.115391

Bone fracture is accompanied by trauma, mechanical stresses, and inflammation – conditions known to induce the mitochondrial permeability transition. This phenomenon occurs due to opening of the mitochondrial permeability transition pore (MPTP) promoted by cyclophilin D (CypD). MPTP opening leads to more inflammation, cell death and potentially to disruption of fracture repair. Here we performed a proof-of-concept study and tested a hypothesis that protecting mitochondria from MPTP opening via inhibition of CypD improves fracture repair. First, our in vitro experiments indicated pro-osteogenic and anti-inflammatory effects in osteoprogenitors upon CypD knock-out or pharmacological inhibition. Using a bone fracture model in mice, we observed that bone formation and biomechanical properties of repaired bones were significantly increased in CypD knock-out mice or wild type mice treated with a CypD inhibitor, NIM811, when compared to controls. These effects were evident in young male but not female mice, however in older (13 month-old) female mice bone formation was also increased during fracture repair. In contrast to global CypD knock-out, mesenchymal lineage-specific (Prx1-Cre driven) CypD deletion did not result in improved fracture repair. Our findings implicate MPTP in bone fracture and suggest systemic CypD inhibition as a modality to promote fracture repair. •MPT inhibition using CypD knock-out or NIM811 exerts pro-osteogenic effect in BMSCs.•Protecting mitochondria from the MPT stimulates bone fracture repair.•CypD knock-out promotes osteoblast activity and bone formation in fracture repair.