Caspase-2 maintains bone homeostasis by inducing apoptosis of oxidatively-damaged osteoclasts

Ramaswamy Sharma, Danielle Callaway, Difernando Vanegas, Michelle Bendele, Marisa Lopez-Cruzan, Diane Horn, Teja Guda, Roberto Fajardo, Sherry Abboud-Werner, Brian Herman

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Osteoporosis is a silent disease, characterized by a porous bone micro-structure that enhances risk for fractures and associated disabilities. Senile, or age-related osteoporosis (SO), affects both men and women, resulting in increased morbidity and mortality. However, cellular and molecular mechanisms underlying senile osteoporosis are not fully known. Recent studies implicate the accumulation of reactive oxygen species (ROS) and increased oxidative stress as key factors in SO. Herein, we show that loss of caspase-2, a cysteine aspartate protease involved in oxidative stress-induced apoptosis, results in total body and femoral bone loss in aged mice (20% decrease in bone mineral density), and an increase in bone fragility (30% decrease in fracture strength). Importantly, we demonstrate that genetic ablation or selective inhibition of caspase-2 using zVDVAD-fmk results in increased numbers of bone-resorbing osteoclasts and enhanced tartrate-resistant acid phosphatase (TRAP) activity. Conversely, transfection of osteoclast precursors with wild type caspase-2 but not an enzymatic mutant, results in a decrease in TRAP activity. We demonstrate that caspase-2 expression is induced in osteoclasts treated with oxidants such as hydrogen peroxide and that loss of caspase-2 enhances resistance to oxidants, as measured by TRAP activity, and decreases oxidative stress-induced apoptosis of osteoclasts. Moreover, oxidative stress, quantified by assessment of the lipid peroxidation marker, 4-HNE, is increased in Casp2-/- bone, perhaps due to a decrease in antioxidant enzymes such as SOD2. Taken together, our data point to a critical and novel role for caspase-2 in maintaining bone homeostasis by modulating ROS levels and osteoclast apoptosis during conditions of enhanced oxidative stress that occur during aging.

Original languageEnglish (US)
Article numbere93696
JournalPLoS One
Volume9
Issue number4
DOIs
StatePublished - Apr 1 2014

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caspase-2
Caspase 2
osteoclasts
Osteoclasts
Oxidative stress
homeostasis
Bone
Homeostasis
apoptosis
bones
Apoptosis
Oxidative Stress
oxidative stress
Bone and Bones
osteoporosis
acid phosphatase
Osteoporosis
Acid Phosphatase
Oxidants
oxidants

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Caspase-2 maintains bone homeostasis by inducing apoptosis of oxidatively-damaged osteoclasts. / Sharma, Ramaswamy; Callaway, Danielle; Vanegas, Difernando; Bendele, Michelle; Lopez-Cruzan, Marisa; Horn, Diane; Guda, Teja; Fajardo, Roberto; Abboud-Werner, Sherry; Herman, Brian.

In: PLoS One, Vol. 9, No. 4, e93696, 01.04.2014.

Research output: Contribution to journalArticle

Sharma, R, Callaway, D, Vanegas, D, Bendele, M, Lopez-Cruzan, M, Horn, D, Guda, T, Fajardo, R, Abboud-Werner, S & Herman, B 2014, 'Caspase-2 maintains bone homeostasis by inducing apoptosis of oxidatively-damaged osteoclasts', PLoS One, vol. 9, no. 4, e93696. https://doi.org/10.1371/journal.pone.0093696
Sharma R, Callaway D, Vanegas D, Bendele M, Lopez-Cruzan M, Horn D et al. Caspase-2 maintains bone homeostasis by inducing apoptosis of oxidatively-damaged osteoclasts. PLoS One. 2014 Apr 1;9(4). e93696. https://doi.org/10.1371/journal.pone.0093696
Sharma, Ramaswamy ; Callaway, Danielle ; Vanegas, Difernando ; Bendele, Michelle ; Lopez-Cruzan, Marisa ; Horn, Diane ; Guda, Teja ; Fajardo, Roberto ; Abboud-Werner, Sherry ; Herman, Brian. / Caspase-2 maintains bone homeostasis by inducing apoptosis of oxidatively-damaged osteoclasts. In: PLoS One. 2014 ; Vol. 9, No. 4.
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