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.
Highlights
Bone is a dynamic tissue that undergoes continual remodeling during life [1] through concerted actions of bone-resorbing osteoclasts and bone-forming osteoblasts
Casp22/2 mice exhibit age-related bone loss Dual-energy X-ray absorptiometry (DXA) analyses of 27-month old mice (Fig. 1A) indicated a significantly lower total body (11.8% decrease) and femoral (20% decrease) bone mineral density (BMD) as compared to wild-type mice (p = 0.0017 and p = 0.0016 respectively). 2D mCT analysis (Fig. 1B, panels a,b) and reconstructed 3D-images of Casp22/2 femur (Fig. 1B, panels c,d) showed higher cortical porosity and a wider metaphyseal compartment (Fig. 1B, panels eh) in 27-month Casp22/2 femurs as compared to Casp2+/+ femur
Since osteoclasts are rich in mitochondria that are the major source of reactive oxygen species (ROS), the intrinsic apoptotic pathway is found to be mostly involved in ROS-induced osteoclast apoptosis [33]
Summary
Bone is a dynamic tissue that undergoes continual remodeling during life [1] through concerted actions of bone-resorbing osteoclasts and bone-forming osteoblasts. Postmenopausal, estrogen-deficiency-related bone loss (type I) has been the focal point of osteoporosis research whereas little is known about age-related, senile (type II) osteoporosis. Type I osteoporosis occurs late in life and develops relatively rapidly, following a dip in estrogen levels after menopause and mostly affects cancellous bone. Age-related osteoporosis begins earlier in life, is independent of sex steroid levels, occurs gradually, and affects cortical and trabecular bone in both men and women [reviewed in 2]. More than 50% of women and 20% of men over the age of 65 are at high risk for senile osteoporosis that is associated with vertebral and hip fractures costing billions of dollars in treatment annually; importantly, osteoporotic fractures result in increased mortality [3]. The molecular mechanisms underlying age-related osteoporosis are not fully known
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