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Related Concept Videos

Caspases01:24

Caspases

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Caspase, a family of cysteine proteases, serve as effectors in apoptosis. The ced3 gene in C.elegans was first identified to be involved in apoptosis. This gene encodes the ced-3 caspase that is similar to the interleukin-1-beta converting enzyme or ICE in mammals. In addition to apoptosis, caspases also function in the inflammatory response. Inflammatory caspases are essential in activating pro-inflammatory cytokines that recruit immune cells and block the replication of pathogens inside...
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Osteoclasts in Bone Remodeling01:31

Osteoclasts in Bone Remodeling

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Osteoclasts are cells responsible for bone resorption and remodeling. They originate from hematopoietic progenitor cells present in the bone marrow. Numerous progenitor cells fuse to form multinucleated cells, each with 10-20 nuclei. A single osteoclast has a diameter of 150 to 200 µM. These cells have ruffled borders that break down the underlying bone tissue and release minerals such as calcium into the blood in bone resorption. Osteoclasts cling to bones with their ruffled edges during...
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The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

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Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
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The Extrinsic Apoptotic Pathway01:17

The Extrinsic Apoptotic Pathway

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The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...
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TGF - β Signaling Pathway01:16

TGF - β Signaling Pathway

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The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors...
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Receptor Downregulation in MVBs01:15

Receptor Downregulation in MVBs

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Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that  lead to cell proliferation, migration, and differentiation. Overexpression of EGFR  stimulates cells to proliferate. Excessive  EGFR...
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A Simple Pit Assay Protocol to Visualize and Quantify Osteoclastic Resorption In Vitro
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Caspase-2 modulates osteoclastogenesis through down-regulating oxidative stress.

Danielle A Callaway1, Manuel A Riquelme1, Ramaswamy Sharma2

  • 1Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.

Bone
|March 23, 2015
PubMed
Summary

Loss of caspase-2 (Casp-2) increases osteoclast formation by raising oxidative stress. This study reveals Casp-2

Keywords:
Caspase-2OsteoclastogenesisOxidative stress

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Area of Science:

  • Cell Biology
  • Bone Biology
  • Biochemistry

Background:

  • Caspase-2 (Casp-2) deficiency in mice leads to osteopenia and elevated osteoclast numbers.
  • Osteoclastogenesis, the process of osteoclast formation, is crucial for bone remodeling.
  • Oxidative stress, particularly mitochondrial reactive oxygen species (ROS), impacts late-stage osteoclast differentiation.

Purpose of the Study:

  • To investigate the role of Caspase-2 (Casp-2) in osteoclast differentiation and its regulation of oxidative stress.
  • To determine the effect of Casp-2 loss on macrophage-to-osteoclast differentiation and osteoclast function.

Main Methods:

  • siRNA-mediated knockdown of Casp-2 in osteoclast precursors.
  • Osteoclast differentiation assays using bone marrow macrophage (BMM) precursors from Casp2(-/-) mice.
  • Measurement of tartrate-resistant acid phosphatase (TRAP) activity, osteoclast size, and nuclearity.
  • Analysis of total and mitochondrial ROS levels, and expression of antioxidant enzymes (catalase, SOD2) and transcription factors (FoxO3a).

Main Results:

  • Casp-2 protein levels decrease during macrophage differentiation into osteoclasts.
  • Casp-2 knockdown or deficiency significantly increases osteoclast numbers, size, and TRAP activity.
  • Loss of Casp-2 enhances precursor fusion and NFATc1 auto-amplification during later stages of differentiation.
  • Casp2(-/-) BMM precursors exhibit elevated total and mitochondrial ROS, with reduced FoxO3a and antioxidant enzyme expression.

Conclusions:

  • Caspase-2 (Casp-2) plays a novel inhibitory role in osteoclast differentiation.
  • The loss of Casp-2 leads to increased osteoclastogenesis, mediated by elevated oxidative stress, particularly mitochondrial ROS.
  • Casp-2 acts as a modulator of ROS production and osteoclast differentiation, impacting bone homeostasis.