PMID- 26094846 OWN - NLM STAT- MEDLINE DCOM- 20161019 LR - 20231213 IS - 1523-4681 (Electronic) IS - 0884-0431 (Print) IS - 0884-0431 (Linking) VI - 30 IP - 12 DP - 2015 Dec TI - Alternative NF-kappaB Regulates RANKL-Induced Osteoclast Differentiation and Mitochondrial Biogenesis via Independent Mechanisms. PG - 2287-99 LID - 10.1002/jbmr.2584 [doi] AB - 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-kappaB pathway proteins, RelB and NF-kappaB-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-kappaB 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-1beta (Ppargc1b) expression, but not PGC-1alpha, PPRC1, or ERRalpha, was significantly reduced in RelB(-/-) and NIK(-/-) OCs. Because PGC-1beta has been reported to positively regulate both mitochondrial biogenesis and differentiation in OCs, we retrovirally overexpressed PGC-1beta 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-1beta, 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-kappaB pathway plays dual, but distinct, roles in controlling the independent processes of OC differentiation and OC mitochondrial biogenesis. Furthermore, the inability of PGC-1beta to drive mitochondrial biogenesis in OCs without RelB indicates a cell-type specificity in mitochondria regulation. CI - (c) 2015 American Society for Bone and Mineral Research. FAU - Zeng, Rong AU - Zeng R AD - Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, MO, USA. AD - Division of Bone and Mineral Research, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA. FAU - Faccio, Roberta AU - Faccio R AD - Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, MO, USA. AD - Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, MO, USA. FAU - Novack, Deborah V AU - Novack DV AD - Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, MO, USA. AD - Division of Bone and Mineral Research, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA. AD - Department of Pathology, Washington University School of Medicine, St. Louis, MO, USA. LA - eng GR - R01 AR053628/AR/NIAMS NIH HHS/United States GR - R01 AR052705/AR/NIAMS NIH HHS/United States GR - R01AR052705/AR/NIAMS NIH HHS/United States GR - T32 AR060719/AR/NIAMS NIH HHS/United States GR - T32AR060719/AR/NIAMS NIH HHS/United States GR - R01AR053628/AR/NIAMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20150806 PL - England TA - J Bone Miner Res JT - Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research JID - 8610640 RN - 0 (Ligands) RN - 0 (NF-kappa B) RN - 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha) RN - 0 (Ppargc1a protein, mouse) RN - 0 (RANK Ligand) RN - 0 (Relb protein, mouse) RN - 0 (Transcription Factors) RN - 147337-75-5 (Transcription Factor RelB) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - S88TT14065 (Oxygen) SB - IM MH - Animals MH - Bone Marrow Cells/cytology MH - Bone Resorption MH - Cell Differentiation MH - Ligands MH - Macrophages/cytology MH - Mice MH - Mice, Transgenic MH - Mitochondria/*metabolism MH - Mutation MH - NF-kappa B/*metabolism MH - *Organelle Biogenesis MH - Osteoclasts/*cytology/metabolism MH - Oxidative Phosphorylation MH - Oxygen/metabolism MH - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha MH - Protein Serine-Threonine Kinases/metabolism MH - RANK Ligand/*metabolism MH - Transcription Factor RelB/metabolism MH - Transcription Factors/metabolism MH - NF-kappaB-Inducing Kinase PMC - PMC4834842 MID - NIHMS773791 OTO - NOTNLM OT - MOLECULAR PATHWAYS-REMODELING OT - OSTEOCLASTS OT - TRANSCRIPTION FACTORS EDAT- 2015/06/23 06:00 MHDA- 2016/11/12 06:00 PMCR- 2016/12/01 CRDT- 2015/06/23 06:00 PHST- 2015/02/03 00:00 [received] PHST- 2015/06/02 00:00 [revised] PHST- 2015/06/19 00:00 [accepted] PHST- 2015/06/23 06:00 [entrez] PHST- 2015/06/23 06:00 [pubmed] PHST- 2016/11/12 06:00 [medline] PHST- 2016/12/01 00:00 [pmc-release] AID - 10.1002/jbmr.2584 [doi] PST - ppublish SO - J Bone Miner Res. 2015 Dec;30(12):2287-99. doi: 10.1002/jbmr.2584. Epub 2015 Aug 6.