title: Caspase-2 modulates osteoclastogenesis through down-regulating oxidative stress.
abstract: The loss of caspase-2 (Casp-2) in mice results in an osteopenic phenotype associated with increased numbers of osteoclasts in vivo. In this study, we show that Casp-2 is involved in osteoclastogenesis. Protein levels of Casp-2 decrease during the differentiation of macrophages to osteoclasts. Furthermore, siRNA-mediated Casp-2 knockdown in osteoclast precursors or differentiation of bone marrow macrophage (BMM) precursors from Casp2(-/-) mice results in increased osteoclast numbers and tartrate-resistant acid phosphatase (TRAP) activity. Casp2(-/-) osteoclasts are larger in size compared to wild-type osteoclasts and exhibited increased numbers of nuclei, perhaps due to increased precursor fusion. The loss of Casp-2 did not alter earlier stages of differentiation, but had a greater consequence on later stages involving NFATc1 auto-amplification and pre-osteoclast fusion. We have previously shown that the loss of Casp-2 results in increased oxidative stress in the bone. Reactive oxygen species (ROS) is known to play a critical role in late osteoclast differentiation and we show that total ROS and specifically, mitochondrial ROS, significantly increased in Casp2(-/-) BMM precursors after RANKL administration, with a concomitant reduction in FoxO3a and its target antioxidant enzymes, catalase and superoxide 2 (SOD2). Because mitochondrial ROS has been identified as a putative regulator of the later stages of differentiation, the heightened ROS levels in Casp2(-/-) cells likely promote precursor fusion and increased osteoclast numbers. In conclusion, our results indicate a novel role of Casp-2 in the osteoclast as a modulator of total and mitochondrial ROS and osteoclast differentiation.
authors: Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
authors: Danielle A
authors: DA
authors: Callaway
authors: Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
authors: Manuel A
authors: MA
authors: Riquelme
authors: Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
authors: Ramaswamy
authors: R
authors: Sharma
authors: Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
authors: Marisa
authors: M
authors: Lopez-Cruzan
authors: Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
authors: Brian A
authors: BA
authors: Herman
authors: Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA. Electronic address: jiangj@uthscsa.edu.
authors: Jean X
authors: JX
authors: Jiang
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D053143:Caspase 2 / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002459:Cell Fusion; D015536:Down-Regulation; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000975:Antioxidants; D017382:Reactive Oxygen Species; D053143:Caspase 2
keywords: Caspase-2; Osteoclastogenesis; Oxidative stress