4.6 Article

Osteolineage depletion of mitofusin2 enhances cortical bone formation in female mice

期刊

BONE
卷 148, 期 -, 页码 -

出版社

ELSEVIER SCIENCE INC
DOI: 10.1016/j.bone.2021.115941

关键词

Mitochondria; Osteogenesis; Osteoblast; Bone formation; Mitofusin

资金

  1. NIAMS, National Institutes of Health [R01 AR052705, R01 AR070030, R01 AR066551]
  2. Shriners Hospitals for Children
  3. NIAMS, National Institutes of Health Metabolic Skeletal Disorders Training Program [T32AR060719]
  4. Hope Center for Neurological Disorders shared instrumentation grant (NCRR, National Institutes of Health) [1S10RR027552]
  5. Musculoskeletal Research Center grant (NIAMS, National Institutes of Health) [P30 AR074992]
  6. Washington University Center for Cellular Imaging (WUCCI) - Children's Discovery Institute of Washington University
  7. St. Louis Children's Hospital [CDI-CORE-2015-505, CDICORE2019813]
  8. Foundation for BarnesJewish Hospital [3770, 4642]
  9. Washington University Musculoskeletal Research Center [P30AR074992]
  10. Office of Research Infrastructure Programs (ORIP) , a part of the NIH Office of the Director [S10OD021629]
  11. Washington University Rheumatic Diseases Research Resourcebased Center [P30AR073752]

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Mitochondria are essential organelles forming highly complex networks inside cells, with GTPase mitofusin 2 (MFN2) regulating mitochondrial morphology and affecting metabolic and signaling functions. The role of mitochondria in bone formation is unclear, but MFN2 levels increase during osteoblast differentiation. Deficiency of MFN2 leads to increased oxygen consumption, mineralization, and expression of osteoblast markers in bone marrow-derived mesenchymal stromal cells.
Mitochondria are essential organelles that form highly complex, interconnected dynamic networks inside cells. The GTPase mitofusin 2 (MFN2) is a highly conserved outer mitochondrial membrane protein involved in the regulation of mitochondrial morphology, which can affect various metabolic and signaling functions. The role of mitochondria in bone formation remains unclear. Since MFN2 levels increase during osteoblast (OB) differentiation, we investigated the role of MFN2 in the osteolineage by crossing mice bearing floxed Mfn2 alleles with those bearing Prx-cre to generate cohorts of conditional knock out (cKO) animals. By ex vivo microCT, cKO female mice, but not males, display an increase in cortical thickness at 8, 18, and 30 weeks, compared to wild-type (WT) littermate controls. However, the cortical anabolic response to mechanical loading was not different between genotypes. To address how Mfn2 deficiency affects OB differentiation, bone marrow-derived mesenchymal stromal cells (MSCs) from both wild-type and cKO mice were cultured in osteogenic media with different levels of ?-glycerophosphate. cKO MSCs show increased mineralization and expression of multiple markers of OB differentiation only at the lower dose. Interestingly, despite showing the expected mitochondrial rounding and fragmentation due to loss of MFN2, cKO MSCs have an increase in oxygen consumption during the first 7 days of OB differentiation. Thus, in the early phases of osteogenesis, MFN2 restrains oxygen consumption thereby limiting differentiation and cortical bone accrual during homeostasis in vivo.

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