Caspase-2 maintains bone homeostasis by inducing apoptosis of oxidatively-damaged osteoclasts.
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 mechani...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2014-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3972236?pdf=render |
| _version_ | 1818519819629101056 |
|---|---|
| author | Ramaswamy Sharma Danielle Callaway Difernando Vanegas Michelle Bendele Marisa Lopez-Cruzan Diane Horn Teja Guda Roberto Fajardo Sherry Abboud-Werner Brian Herman |
| author_facet | Ramaswamy Sharma Danielle Callaway Difernando Vanegas Michelle Bendele Marisa Lopez-Cruzan Diane Horn Teja Guda Roberto Fajardo Sherry Abboud-Werner Brian Herman |
| author_sort | Ramaswamy Sharma |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T01:29:10Z |
| format | Article |
| id | doaj.art-61ffe57d32a54e11843acbd478a9315a |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-11T01:29:10Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-61ffe57d32a54e11843acbd478a9315a2022-12-22T01:25:26ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0194e9369610.1371/journal.pone.0093696Caspase-2 maintains bone homeostasis by inducing apoptosis of oxidatively-damaged osteoclasts.Ramaswamy SharmaDanielle CallawayDifernando VanegasMichelle BendeleMarisa Lopez-CruzanDiane HornTeja GudaRoberto FajardoSherry Abboud-WernerBrian HermanOsteoporosis 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.http://europepmc.org/articles/PMC3972236?pdf=render |
| spellingShingle | Ramaswamy Sharma Danielle Callaway Difernando Vanegas Michelle Bendele Marisa Lopez-Cruzan Diane Horn Teja Guda Roberto Fajardo Sherry Abboud-Werner Brian Herman Caspase-2 maintains bone homeostasis by inducing apoptosis of oxidatively-damaged osteoclasts. PLoS ONE |
| title | Caspase-2 maintains bone homeostasis by inducing apoptosis of oxidatively-damaged osteoclasts. |
| title_full | Caspase-2 maintains bone homeostasis by inducing apoptosis of oxidatively-damaged osteoclasts. |
| title_fullStr | Caspase-2 maintains bone homeostasis by inducing apoptosis of oxidatively-damaged osteoclasts. |
| title_full_unstemmed | Caspase-2 maintains bone homeostasis by inducing apoptosis of oxidatively-damaged osteoclasts. |
| title_short | Caspase-2 maintains bone homeostasis by inducing apoptosis of oxidatively-damaged osteoclasts. |
| title_sort | caspase 2 maintains bone homeostasis by inducing apoptosis of oxidatively damaged osteoclasts |
| url | http://europepmc.org/articles/PMC3972236?pdf=render |
| work_keys_str_mv | AT ramaswamysharma caspase2maintainsbonehomeostasisbyinducingapoptosisofoxidativelydamagedosteoclasts AT daniellecallaway caspase2maintainsbonehomeostasisbyinducingapoptosisofoxidativelydamagedosteoclasts AT difernandovanegas caspase2maintainsbonehomeostasisbyinducingapoptosisofoxidativelydamagedosteoclasts AT michellebendele caspase2maintainsbonehomeostasisbyinducingapoptosisofoxidativelydamagedosteoclasts AT marisalopezcruzan caspase2maintainsbonehomeostasisbyinducingapoptosisofoxidativelydamagedosteoclasts AT dianehorn caspase2maintainsbonehomeostasisbyinducingapoptosisofoxidativelydamagedosteoclasts AT tejaguda caspase2maintainsbonehomeostasisbyinducingapoptosisofoxidativelydamagedosteoclasts AT robertofajardo caspase2maintainsbonehomeostasisbyinducingapoptosisofoxidativelydamagedosteoclasts AT sherryabboudwerner caspase2maintainsbonehomeostasisbyinducingapoptosisofoxidativelydamagedosteoclasts AT brianherman caspase2maintainsbonehomeostasisbyinducingapoptosisofoxidativelydamagedosteoclasts |