Caspase-2 modulates osteoclastogenesis through down-regulating oxidative stress

Danielle A. Callaway, Manuel A. Riquelme, Ramaswamy Sharma, Marisa Lopez-Cruzan, Brian A. Herman, Jean X. Jiang

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)40-48
Number of pages9
StatePublished - Jul 1 2015

Bibliographical note

Funding Information:
This study was funded by NIH grants F30AG039948 to DAC, PO1AG019316 to BAH, and EY012085 and Welch Foundation grant AQ-1507 to JXJ.

Publisher Copyright:
© 2015 Elsevier Inc.


  • Caspase-2
  • Osteoclastogenesis
  • Oxidative stress


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