TY - JOUR
T1 - Osteolineage depletion of mitofusin2 enhances cortical bone formation in female mice
AU - Zarei, Allahdad
AU - Ballard, Anna
AU - Cox, Linda
AU - Bayguinov, Peter
AU - Harris, Taylor
AU - Davis, Jennifer L.
AU - Roper, Philip
AU - Fitzpatrick, James
AU - Faccio, Roberta
AU - Veis, Deborah J.
N1 - Funding Information:
This work was supported by NIAMS , National Institutes of Health Grants R01 AR052705 (to D. J. V.) and R01 AR070030 (to D. J. V. and R. F.) and R01 AR066551 (to R. F.), funding from Shriners Hospitals for Children (to D. J. V. and R. F.), as well as NIAMS, National Institutes of Health Metabolic Skeletal Disorders Training Program Grant T32AR060719 (to A. B. and P.R). Slide scanning was made possible with support from a Hope Center for Neurological Disorders shared instrumentation grant (NCRR, National Institutes of Health Grant 1S10RR027552 ) and μCT and histology by a Musculoskeletal Research Center grant (NIAMS, National Institutes of Health Grant P30 AR074992 (to R. F. and D. J. V.). POB and JAJF are supported by the Washington University Center for Cellular Imaging (WUCCI) which is funded in part by The Children's Discovery Institute of Washington University and St. Louis Children's Hospital ( CDI-CORE-2015-505 and CDI-CORE-2019-813 ), the Foundation for Barnes-Jewish Hospital ( 3770 and 4642 ), the Washington University Rheumatic Diseases Research Resource-based Center ( P30AR073752 ) and the Washington University Musculoskeletal Research Center ( P30AR074992 ). The Zeiss LSM880 microscope used in the course of these studies was purchased with support from the Office of Research Infrastructure Programs (ORIP), a part of the NIH Office of the Director ( S10OD021629 ).
Publisher Copyright:
© 2021
PY - 2021/7
Y1 - 2021/7
N2 - 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 β-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.
AB - 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 β-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.
KW - Bone formation
KW - Mitochondria
KW - Mitofusin
KW - Osteoblast
KW - Osteogenesis
UR - http://www.scopus.com/inward/record.url?scp=85104052649&partnerID=8YFLogxK
U2 - 10.1016/j.bone.2021.115941
DO - 10.1016/j.bone.2021.115941
M3 - Article
C2 - 33813068
AN - SCOPUS:85104052649
SN - 8756-3282
VL - 148
JO - Bone
JF - Bone
M1 - 115941
ER -