Osteoclast
Osteoblasts and osteoclasts on trabecula of lower jaw of calf embryo.
Gray's	subject #18 88
Dorlands/Elsevier	o_08/12600400

An osteoclast (from the Greek words for "bone" and "broken") is a type of bone cell that removes bone tissue by removing its mineralized matrix. Introduction ( classes Long bones body or Diaphysis Medullary canal Elsevier, the world's largest Publisher of Medical and Scientific literature, forms part of the Reed Elsevier group There are five types of bone cells. Osteoblasts - These are commonly called bone-forming cells Osseous tissue, or bone tissue is the major structural and supportive Connective tissue of the body This process is known as bone resorption. Bone resorption is the process by which Osteoclasts break down Bone and release the Minerals resulting in a transfer of calcium from bone fluid to the blood Osteoclasts and osteoblasts are instrumental in controlling the amount of bone tissue: osteoblasts form bone, osteoclasts resorb bone. An osteoblast (from the Greek words for " Bone " and "germ" or embryonic is a mononucleate cell that is responsible for bone formation Osteoclasts are formed by the fusion of cells of the monocyte-macrophage cell line. Monocyte is a type of Leukocyte, part of the Human body 's Immune system. Macrophages ( Greek: "big eaters" from makros "large" + phagein "eat" ( Mø) are cells within the tissues that ^[1] Osteoclasts are characterized by high expression of tartrate resistant acid phosphatase (TRAP) and cathepsin K. Protein expression is a subcomponent of Gene expression. It consists of the stages after DNA has been translated into Amino acid chains which are ultimately folded Tartrate resistant acid phosphatase is a Glycosylated monomeric metalloenzyme expressed in mammals

Morphology

Osteoclast displaying many nuclei within its "foamy" cytoplasm

Tartrate resistant acid phosphatase positive osteoclast in cell culture

Illustrated cross-section of an activated osteoclast

An osteoclast is a large cell that is characterized by multiple nuclei and a cytoplasm with a homogeneous, "foamy" appearance. Tartrate resistant acid phosphatase is a Glycosylated monomeric metalloenzyme expressed in mammals This appearance is due to a high concentration of vesicles and vacuoles. A vesicle is a small bubble of liquid within a cell A more formal definition in Cell biology, would be that a vesicle is a relatively small intracellular membrane-enclosed In general vacuole functions include Removing unwanted structural debris Isolating materials that might be harmful or a threat to the cell Containing ^[2][3] At a site of active bone resorption, the osteoclast forms a specialized cell membrane, the "ruffled border", which touches the surface of the bone tissue. The cell membrane (also called the plasma membrane, plasmalemma, or "phospholipid bilayer" is a Selectively permeable Lipid bilayer ^[1] The ruffled border, which facilitates removal of the bony matrix, is a morphologic characteristic of an osteoclast that is actively resorbing bone. The ruffled border increases surface area interface for bone resorption. The mineral portion of the matrix (called hydroxyapatite) includes calcium and phosphate ions. Hydroxylapatite, also called hydroxyapatite, is a Mineral. It is a naturally occurring form of calcium Apatite with the formula Ca5(PO43(OH Calcium (ˈkælsiəm is the Chemical element with the symbol Ca and Atomic number 20 A phosphate, an Inorganic chemical, is a salt of Phosphoric acid. These ions are absorbed into small vesicles (see endocytosis) which move across the cell and eventually are released into the extracellular fluid, thus increasing levels of the ions in the blood. A vesicle is a small bubble of liquid within a cell A more formal definition in Cell biology, would be that a vesicle is a relatively small intracellular membrane-enclosed Endocytosis is a process where cells absorb material ( Molecules such as proteins from the outside by engulfing it with their Cell membrane. Extracellular fluid (ECF usually denotes all body fluid outside of cells

Formation

Osteoclasts formation requires the presence of RANK ligand (receptor activator of nuclear factor κβ) and M-CSF (Macrophage colony-stimulating factor). Macrophage colony-stimulating factor, or M-CSF is a secreted Cytokine which influences Hemopoietic stem cells to differentiate into Macrophages or other These membrane bound proteins are produced by neighbouring stromal cells and osteoblasts; thus requiring direct contact between these cells and osteoclast precursors. In Cell biology, stromal cells are Connective tissue cells of an organ found in the loose connective tissue An osteoblast (from the Greek words for " Bone " and "germ" or embryonic is a mononucleate cell that is responsible for bone formation

M-CSF acts through its receptor on the osteoclast, c-fms (colony stimulating factor 1 receptor), a transmembrane tyrosine kinase-receptor, leading to secondary messenger activation of tyrosine kinase Src. A tyrosine kinase is an Enzyme that can transfer a Phosphate group from ATP to a Tyrosine residue in a Protein. In Cell physiology, a secondary messenger system (also known as a second messenger system) is a method of cellular signaling whereby a diffusable signaling molecule Both of these molecules are necessary for osteoclastogenesis and are widely involved in the differentiation of monocyte/macrophage derived cells.

RANKL is a member of the tumour necrosis family (TNF), and is essential in osteoclastogenesis. RANKL ( Receptor Activator for Nuclear Factor κ B Ligand) also known as TNF-related activation-induced cytokine (TRANCE osteoprotegerin ligand (OPGL and ODF (osteoclast Tumor necrosis factors (or the TNF-family) refers to a group of Cytokines family that can cause Apoptosis. RANKL knockout mice exhibit a phenotype of osteopetrosis and defects of tooth eruption, along with an absence or deficiency of osteoclasts. Osteopetrosis also known as marble bone disease and Albers-Schonberg disease is an extremely Rare inherited disorder whereby the RANKL activates NF-κβ (nuclear factor-κβ) and NFATc1 (nuclear factor of activated t cells, cytoplasmic, calcineurin-dependent 1) through RANK. RANK (Receptor Activator of Nuclear Factor κ B, also known as TRANCE Receptor is a type I membrane protein which is expressed on the surface of Osteoclasts and is involved NF-κβ activation is stimulated almost immediately after RANKL-RANK interaction occurs, and is not upregulated. NFATc1 stimulation, however, begins ~24-48 hours after binding occurs and its expression has been shown to be RANKL dependent.

Osteoclast differentiation is inhibited by osteoprotegerin (OPG), which binds to RANKL thereby preventing interaction with RANK. Osteoprotegerin (OPG, also known as osteoclastogenesis inhibitory factor (OCIF is a Cytokine, which can inhibit the production of Osteoclasts.

Function

Once activated, they move to areas of microfracture in the bone by chemotaxis. Chemotaxis, a kind of Taxis, is the phenomenon in which bodily cells bacteria, and other single-cell or Multicellular organisms direct their movements Osteoclasts lie in a small cavity called Howship's lacuna, formed from the digestion of the underlying bone. The sealing zone is the attachment of the osteoclast's plasmalemma to the underlying bone. The cell membrane (also called the plasma membrane, plasmalemma, or "phospholipid bilayer" is a Selectively permeable Lipid bilayer Bones are rigid organs that form part of the Endoskeleton of Vertebrates They function to move support and protect the various organs of the body produce Sealing zones are bounded by belts of specialized adhesion structures called podosomes. Podosomes are the primary sites of Integrin stimulated Actin polymerization in Leukocytes of the monocytic lineage Attachment to the bone matrix is facilitated by integrin receptors, such as αvβ3, via the specific amino acid motif Arg-Gly-Asp in bone matrix proteins, such as osteopontin. In an unbranched chain-like biological Molecule, such as a Protein or a strand of RNA, a structural motif is a three-dimensional structural Secreted phosphoprotein 1 (osteopontin bone sialoprotein I early T-lymphocyte activation 1, also known as SPP1 and commonly referred to as osteopontin, is The osteoclast releases hydrogen ions (H₂O + CO₂ → HCO₃^- + H⁺) through the ruffled border into the cavity, acidifying and dissolving the mineralized bone matrix into Ca²⁺, H₃PO₄, H₂CO₃ and water. Hydrogen ion is recommended by IUPAC as a general term for all Ions of Hydrogen and its Isotopes Depending on the Charge of the ion Water ( H2[[oxygen O]] H OH) is the most abundant Molecule on Earth 's surface composing of about 70% of the Earth's surface as Carbon dioxide ( Chemical formula:) is a Chemical compound composed of two Oxygen Atoms covalently bonded to a single In Inorganic chemistry, bicarbonate ( IUPAC -recommended nomenclature hydrogencarbonate) is an intermediate form in the Deprotonation Hydrogen ion is recommended by IUPAC as a general term for all Ions of Hydrogen and its Isotopes Depending on the Charge of the ion Bones are rigid organs that form part of the Endoskeleton of Vertebrates They function to move support and protect the various organs of the body produce In Biology, matrix (plural matrices) is the material between animal or plant cells, the material (or tissue in which more specialized structures are embedded Calcium (ˈkælsiəm is the Chemical element with the symbol Ca and Atomic number 20 Hydrogen ions are pumped against a high concentration gradient by proton pumps, specifically a unique vacuolar-ATPase. This article is about proton pumps in general For the proton P-type ATPase see Proton ATPase. ATPases are a class of Enzymes that catalyze the Decomposition of Adenosine triphosphate (ATP into Adenosine diphosphate (ADP and This enzyme has been targeted in the prevention of osteoporosis. Osteoporosis is a Disease of Bone that leads to an increased risk of fracture. In addition, several hydrolytic enzymes, such as members of the cathepsin and matrix metalloprotease(MMP) groups , are released to digest the organic components of the matrix. In Biochemistry, a hydrolase is an Enzyme that catalyzes the Hydrolysis of a Chemical bond. A cathepsin (Union of two Greek words kata-down and hepseinboil is a cysteine or Aspartic protease, a type of Protein that breaks apart other proteins In Biology, matrix (plural matrices) is the material between animal or plant cells, the material (or tissue in which more specialized structures are embedded These enzymes are released into the compartment by lysosomes. Lysosomes are Organelles that contain Digestive enzymes (acid Hydrolases. Of these hydrolytic enzymes, cathepsin K is of most importance. Cathepsin K, also known as CTSK, is a human enzyme controlled by a Gene.

Cathepsin K and other cathepsins

Cathepsin K is a collagenolytic, papain-like, cysteine protease that is mainly expressed in osteoclasts, and is secreted into the resorptive pit. Cathepsin K, also known as CTSK, is a human enzyme controlled by a Gene. Papain is a Cysteine protease ( Hydrolase Enzyme present in Papaya ( Carica papaya) and Mountain papaya ( Vasconcellea Mutations in the cathepsin K gene are associated with pycnodysostosis, a hereditary osteopetrotic disease, characterised by lack of functional cathepsin K expression. Osteopetrosis also known as marble bone disease and Albers-Schonberg disease is an extremely Rare inherited disorder whereby the Knockout studies of cathepsin K in mice lead to an osteopetrotic phenotype, which, is partially compensated by increased expression of proteases other that cathepsin K and enhanced osteoclastogenesis.

Cathepsin K has an optimal enzymatic activity in acidic conditions. It is synthesized as a proenzyme with a molecular weight of 37kDa, and upon activation by autocatalytic cleavage, is transformed into the mature, active form with a molecular weight of ~27kDa.

In the osteoclast, cathepsin K functions in the resorptive process. Upon polarization of the osteoclast over the site of resorption, cathepsin K is secreted from the ruffled border into the resorptive pit. Here, it is the major protease involved in the degradation of type I collagen and other noncollagenous proteins, which have been demineralized by the acidic environment of the resorptive pit. A protease is any Enzyme that conducts Proteolysis, that is begins protein Catabolism by Hydrolysis of the Peptide bonds that link From the resorptive pit, cathepsin K transmigrates across the ruffled border, through the osteoclast via intercellular vesicles and is then released by the functional secretory domain. Within these intercellular vesicles, cathepsin K, along with ROS generation by TRAP further degrades bone resorption products. Reactive oxygen species (ROS are ions or very small molecules that include Oxygen Ions free radicals, and Peroxides both inorganic and Tartrate resistant acid phosphatase is a Glycosylated monomeric metalloenzyme expressed in mammals

Numerous other cathepsins are expressed in osteoclasts. A cathepsin (Union of two Greek words kata-down and hepseinboil is a cysteine or Aspartic protease, a type of Protein that breaks apart other proteins These include cathepsin B, C, D, E, G, and L. Cathepsin B, also known as CTSB, is a human Gene. Function Cathepsin C, also known as CTSC, is a human Gene. The function of these cysteine and aspartic proteases is generally unknown within bone, and they are expressed at much lower levels that cathepsin K. Proteases are Enzymes that degrade polypeptides. Cysteine proteases have a common catalytic mechanism that involves a nucleophilic Cysteine Aspartic proteases are a family of eukaryotic Protease Enzymes that utilize an Aspartate residue for catalysis of their peptide substrates

Studies on cathepsin L knockout mice have been mixed, with a report of reduced trabecular bone in homozygous and heterozygous cathepsin L knockout mice compared to wild-type and another report finding no skeletal abnormalities. A knockout mouse is a genetically engineered mouse in which one or more Genes have been turned off through a Gene knockout. Cancellous Bone is a type of Osseous tissue with a low density and strength but very high Surface area, that fills the inner cavity of long bones Zygosity refers to the genetic condition of a Zygote. In genetics zygosity describes the similarity or dissimilarity of DNA between Homologous Zygosity refers to the genetic condition of a Zygote. In genetics zygosity describes the similarity or dissimilarity of DNA between Homologous

Matrix metalloproteinases

The matrix metalloproteinases (MMPs) comprise a family of more that 20 zinc-dependent endopeptidases. Matrix metalloproteinases (MMPs are Zinc -dependent Endopeptidases other family members are Adamalysins Serralysins and Astacins The role of matrix metalloproteinases (MMPs) in osteoclast biology is ill-defined, but in other tissue they have been linked with tumor promoting activities, such as activation of growth factors and are required for tumor metastasis and angiogenesis. The term growth factor refers to a naturally occurring Protein capable of stimulating cellular growth proliferation and Cellular differentiation.

MMP-9 is associated with the bone microenvironment. It is expressed by osteoclasts, and is known to be required for osteoclast migration and is a powerful gelatinase. Cell migration is a central process in the development and maintenance of Multicellular organisms Tissue formation during embryonic development, Wound healing Transgenic mice lacking MMP-9 develop defects in bone development, intraosseous angiogenesis, and fracture repair. Angiogenesis is a physiological process involving the growth of new Blood vessels from pre-existing vessels

MMP-13 is believed to be involved in bone resorption and in osteoclast differentiation, as knockout mice revealed decreased osteoclast numbers, osteopetrosis, and decreased bone resorption.

MMPs expressed by the osteoclast include MMP-9, -10, -12, and -14. apart from MMP-9, little is know about their relevance to the osteoclast, however, high levels of MMP-14 are found at the sealing zone.

Regulation

Osteoclasts are regulated by several hormones, including parathyroid hormone (PTH) from the parathyroid gland, calcitonin from the thyroid gland, and growth factor interleukin 6 (IL-6). Hormones (from Greek ὁρμή - "impetus" are chemicals released by cells that affect cells in other parts of the body Parathyroid hormone (PTH, or parathormone, is secreted by the Parathyroid glands as a Polypeptide containing 84 Amino acids. Calcitonin is a 32-amino acid linear polypeptide Hormone that is produced in Humans primarily by the parafollicular (also known as C-cells of the Interleukins are a group of Cytokines (secreted Signaling molecules) that were first seen to be expressed by White blood cells ( Leukocytes hence This last hormone, IL-6, is one of the factors in the disease osteoporosis, which is an imbalance between bone resorption and bone formation. Osteoporosis is a Disease of Bone that leads to an increased risk of fracture. Osteoclast activity is also mediated by the interaction of two molecules produced by osteoblasts, namely osteoprotegerin and RANK ligand. Osteoprotegerin (OPG, also known as osteoclastogenesis inhibitory factor (OCIF is a Cytokine, which can inhibit the production of Osteoclasts. RANKL ( Receptor Activator for Nuclear Factor κ B Ligand) also known as TNF-related activation-induced cytokine (TRANCE osteoprotegerin ligand (OPGL and ODF (osteoclast Note that these molecules also regulate differentiation of the osteoclast. ^[4]

Alternate use of term

An osteoclast can also be an instrument used to fracture and reset bones (the origin is Greek osteon:bone and klastos:broken). To avoid confusion, the cell was originally termed osotoclast. When the surgical instrument went out of use, the cell became known by its present name.

References

External links

• MedicineNet
• MeSH Osteoclasts
• The Life of Osteoclast