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PGC1? Organizes the Osteoclast Cytoskeleton by Mitochondrial Biogenesis and Activation.

ABSTRACT: Osteoclasts are mitochondria-rich cells, but the role of these energy-producing organelles in bone resorption is poorly defined. To this end, we conditionally deleted the mitochondria-inducing co-activator, PGC1?, in myeloid lineage cells to generate PGC1?LysM mice. In contrast to previous reports, PGC1?-deficient macrophages differentiate normally into osteoclasts albeit with impaired resorptive function due to cytoskeletal disorganization. Consequently, bone mass of PGC1?LysM mice is double that of wild type. Mitochondrial biogenesis and function are diminished in PGC1?LysM osteoclasts. All abnormalities are normalized by PGC1? transduction. Furthermore, OXPHOS inhibitors reproduce the phenotype of PGC1? deletion. PGC1?'s organization of the osteoclast cytoskeleton is mediated by expression of GIT1, which also promotes mitochondrial biogenesis. Thus, osteoclast mitochondria regulate the cell's resorptive activity by promoting cytoskeletal organization. © 2018 American Society for Bone and Mineral Research.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC6002881 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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PGC1β Organizes the Osteoclast Cytoskeleton by Mitochondrial Biogenesis and Activation.

Zhang Yan Y Rohatgi Nidhi N Veis Deborah J DJ Schilling Joel J Teitelbaum Steven L SL Zou Wei W

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 20180311 6

Osteoclasts are mitochondria-rich cells, but the role of these energy-producing organelles in bone resorption is poorly defined. To this end, we conditionally deleted the mitochondria-inducing co-activator, PGC1β, in myeloid lineage cells to generate PGC1β<sup>LysM</sup> mice. In contrast to previous reports, PGC1β-deficient macrophages differentiate normally into osteoclasts albeit with impaired resorptive function due to cytoskeletal disorganization. Consequently, bone mass of PGC1β<sup>LysM</ ...[more]

PMID: 29521005

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Project description:Mitochondrial biogenesis, the generation of new mitochondrial DNA and proteins, has been linked to osteoclast (OC) differentiation and function. In this study we used mice with mutations in key alternative NF-?B pathway proteins, RelB and NF-?B-inducing kinase (NIK), to dissect the complex relationship between mitochondrial biogenesis and osteoclastogenesis. In OC precursors lacking either NIK or RelB, receptor activator of NF-?B ligand (RANKL) was unable to increase mitochondrial DNA or oxidative phosphorylation (OxPhos) protein expression, which was associated with lower oxygen consumption rates. Transgenic OC precursors expressing constitutively active NIK showed normal RANKL-induced mitochondrial biogenesis (OxPhos expression and mitochondria copy number) compared to controls, but larger mitochondrial dimensions and increased oxygen consumption rates, suggesting increased mitochondrial function. To deduce the mechanism for mitochondrial biogenesis defects in NIK-deficient and RelB-deficient precursors, we examined expression of genes known to control this process. PGC-1? (Ppargc1b) expression, but not PGC-1?, PPRC1, or ERR?, was significantly reduced in RelB(-/-) and NIK(-/-) OCs. Because PGC-1? has been reported to positively regulate both mitochondrial biogenesis and differentiation in OCs, we retrovirally overexpressed PGC-1? in RelB(-/-) cells, but surprisingly found that it did not affect differentiation, nor did it restore RANKL-induced mitochondrial biogenesis. To determine whether the blockade in osteoclastogenesis in RelB-deficient cells precludes mitochondrial biogenesis, we rescued RelB(-/-) differentiation via overexpression of NFATc1. Mitochondrial parameters in neither WT nor RelB-deficient cultures were affected by NFATc1 overexpression, and bone resorption in RelB(-/-) was not restored. Furthermore, NFATc1 co-overexpression with PGC-1?, although allowing OC differentiation, did not rescue mitochondrial biogenesis or bone resorption in RelB(-/-) OCs, by CTX-I levels. Thus, our results indicate that the alternative NF-?B pathway plays dual, but distinct, roles in controlling the independent processes of OC differentiation and OC mitochondrial biogenesis. Furthermore, the inability of PGC-1? to drive mitochondrial biogenesis in OCs without RelB indicates a cell-type specificity in mitochondria regulation.

Dataset Information

PGC1? Organizes the Osteoclast Cytoskeleton by Mitochondrial Biogenesis and Activation.

Publications

PGC1β Organizes the Osteoclast Cytoskeleton by Mitochondrial Biogenesis and Activation.

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