title: Enhanced osteoclastogenesis by mitochondrial retrograde signaling through transcriptional activation of the cathepsin K gene.
abstract: Mitochondrial dysfunction has emerged as an important factor in wide ranging human pathologies. We have previously defined a retrograde signaling pathway that originates from dysfunctional mitochondria (Mt-RS) and causes a global nuclear transcriptional reprograming as its end point. Mitochondrial dysfunction causing disruption of mitochondrial membrane potential and consequent increase in cytosolic calcium [Ca(2) ](c) activates calcineurin and the transcription factors NF-κB, NFAT, CREB, and C/EBPδ. In macrophages, this signaling complements receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclastic differentiation. Here, we show that the Mt-RS activated transcriptional coactivator heterogeneous ribonucleoprotein A2 (hnRNP A2) is induced by hypoxia in murine macrophages. We demonstrate that the cathepsin K gene (Ctsk), one of the key genes upregulated during osteoclast differentiation, is transcriptionally activated by Mt-RS factors. HnRNP A2 acts as a coactivator with nuclear transcription factors, cRel, and C/EBPδ for Ctsk promoter activation under hypoxic conditions. Notably, our study shows that hypoxia-induced activation of the stress target factors mediates effects similar to that of RANKL with regard to Ctsk activation. We therefore suggest that mitochondrial dysfunction and activation of Mt-RS, induced by various pathophysiologic conditions, is a potential risk factor for osteoclastogenesis and bone loss.
authors: Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Manti
authors: M
authors: Guha
authors: Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Satish
authors: S
authors: Srinivasan
authors: Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Alexander
authors: A
authors: Koenigstein
authors: The Mount Sinai Bone Program, Mount Sinai School of Medicine, New York, New York.
authors: Mone
authors: M
authors: Zaidi
authors: Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Narayan G
authors: NG
authors: Avadhani
mesh_terms: D000818:Animals; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D056657:Cathepsin K / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017930:Genes, Reporter; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D010012:Osteogenesis; D011401:Promoter Regions, Genetic; D053245:RANK Ligand / Q000378:metabolism; D000067996:RAW 264.7 Cells; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation
chemical_list: C497253:Cebpd protein, mouse; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D053245:RANK Ligand; D012333:RNA, Messenger; D011994:Recombinant Proteins; C505689:Tnfsf11 protein, mouse; C439768:hnRNP A2; D051743:CCAAT-Enhancer-Binding Protein-delta; D056657:Cathepsin K; C534132:Ctsk protein, mouse
keywords: Ctsk promoter; Guha, M., S. Srinivasan, A. Koenigstein, M. Zaidi & N.G. Avadhani. 2015. Enhanced osteoclastogenesis by mitochond-rial retrograde signaling through transcriptional activation of the cathepsin K gene. In “MARROW,” ed. by M. Zaidi. Ann. N.Y. Acad. Sci. ; hnRNP A2; hypoxia; mitochondrial retrograde signaling; osteoclastogenesis