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PrecursorOsteoclast_header_cell_0_2_0 osteoclast progenitorsOsteoclast_cell_0_2_1
LocationOsteoclast_header_cell_0_3_0 BoneOsteoclast_cell_0_3_1
FunctionOsteoclast_header_cell_0_4_0 Breakdown of bone tissueOsteoclast_cell_0_4_1
LatinOsteoclast_header_cell_0_6_0 osteoclastusOsteoclast_cell_0_6_1
MeSHOsteoclast_header_cell_0_7_0 Osteoclast_cell_0_7_1
THOsteoclast_header_cell_0_8_0 Osteoclast_cell_0_8_1
FMAOsteoclast_header_cell_0_9_0 Osteoclast_cell_0_9_1

An osteoclast (from Ancient Greek ὀστέον (osteon) 'bone', and κλαστός (clastos) 'broken') is a type of bone cell that breaks down bone tissue. Osteoclast_sentence_0

This function is critical in the maintenance, repair, and remodelling of bones of the vertebral skeleton. Osteoclast_sentence_1

The osteoclast disassembles and digests the composite of hydrated protein and mineral at a molecular level by secreting acid and a collagenase, a process known as bone resorption. Osteoclast_sentence_2

This process also helps regulate the level of blood calcium. Osteoclast_sentence_3

Osteoclasts are found on those surfaces of bone which are undergoing resorption. Osteoclast_sentence_4

On such surfaces, the osteoclasts are seen to be located in shallow depressions called resorption bays (Howship's lacunae). Osteoclast_sentence_5

The resorption bays are created by erosive action of osteoclasts on the underlying bone. Osteoclast_sentence_6

The border of the lower part of an osteoclast exhibits finger-like processes due to presence of deep infoldings of the cell membrane; this border is called ruffled border. Osteoclast_sentence_7

The ruffled border lies in contact with the bone surface within a resorption bay. Osteoclast_sentence_8

The periphery of the ruffled border is surrounded by a ring-like zone of cytoplasm which is devoid of cell organelles but is rich in actin filaments. Osteoclast_sentence_9

This zone is called clear zone or sealing zone. Osteoclast_sentence_10

The actin filaments enable the cell membrane surrounding the sealing zone to be anchored firmly to the bony wall of Howship's lacunae. Osteoclast_sentence_11

In this way, a closed subosteoclastic compartment is created between the ruffled border and the bone that is undergoing resorption. Osteoclast_sentence_12

The osteoclasts secrete hydrogen ions, collagenase, cathepsin K and hydrolytic enzymes into this compartment. Osteoclast_sentence_13

Resorption of bone matrix by the osteoclasts involves two steps: (1) dissolution of inorganic components (minerals), and (2) digestion of organic component of the bone matrix. Osteoclast_sentence_14

The osteoclasts pump hydrogen ions into subosteoclastic compartment and thus create an acidic microenvironment, which increases solubility of bone mineral, resulting in the release and re-entry of bone minerals into the cytoplasm of osteoclasts to be delivered to nearby capillaries. Osteoclast_sentence_15

After the removal of minerals, collagenase and gelatinase are secreted into the subosteoclastic compartment. Osteoclast_sentence_16

These enzymes digest and degrade collagen and other organic components of decalcified bone matrix. Osteoclast_sentence_17

The degradation products are phagocytosed by osteoclasts at the ruffled border. Osteoclast_sentence_18

Because of their phagocytic properties, osteoclasts are considered to be a component of the mononuclear phagocyte system (MPS). Osteoclast_sentence_19

The activity of osteoclasts is controlled by hormones and cytokines. Osteoclast_sentence_20

Calcitonin, a hormone of thyroid gland, suppresses the osteoclastic activity. Osteoclast_sentence_21

The osteoclasts do not have receptors for parathyroid hormone (PTH). Osteoclast_sentence_22

However, PTH stimulates the osteoblasts to secrete the cytokine called osteoclast-stimulating factor, which is a potent stimulator of the osteoclastic activity. Osteoclast_sentence_23

An odontoclast (/odon·to·clast/; o-don´to-klast) is an osteoclast associated with absorption of the roots of deciduous teeth. Osteoclast_sentence_24

Structure Osteoclast_section_0

An osteoclast is a large multinucleated cell and human osteoclasts on bone typically have five nuclei and are 150–200 µm in diameter. Osteoclast_sentence_25

When osteoclast-inducing cytokines are used to convert macrophages to osteoclasts, very large cells that may reach 100 µm in diameter occur. Osteoclast_sentence_26

These may have dozens of nuclei, and typically express major osteoclast proteins but have significant differences from cells in living bone because of the not-natural substrate. Osteoclast_sentence_27

The size of the multinucleated assembled osteoclast allows it to focus the ion transport, protein secretory and vesicular transport capabilities of many macrophages on a localized area of bone. Osteoclast_sentence_28

Location Osteoclast_section_1

In bone, osteoclasts are found in pits in the bone surface which are called resorption bays, or Howship's lacunae. Osteoclast_sentence_29

Osteoclasts are characterized by a cytoplasm with a homogeneous, "foamy" appearance. Osteoclast_sentence_30

This appearance is due to a high concentration of vesicles and vacuoles. Osteoclast_sentence_31

These vacuoles include lysosomes filled with acid phosphatase. Osteoclast_sentence_32

This permits characterization of osteoclasts by their staining for high expression of tartrate resistant acid phosphatase (TRAP) and cathepsin K. Osteoclast_sentence_33

Osteoclast rough endoplasmic reticulum is sparse, and the Golgi complex is extensive. Osteoclast_sentence_34

At a site of active bone resorption, the osteoclast forms a specialized cell membrane, the "ruffled border", that opposes the surface of the bone tissue. Osteoclast_sentence_35

This extensively folded or ruffled border facilitates bone removal by dramatically increasing the cell surface for secretion and uptake of the resorption compartment contents and is a morphologic characteristic of an osteoclast that is actively resorbing bone. Osteoclast_sentence_36

Development Osteoclast_section_2

Since their discovery in 1873 there has been considerable debate about their origin. Osteoclast_sentence_37

Three theories were dominant: from 1949 to 1970 the connective tissue origin was popular, which stated that osteoclasts and osteoblasts are of the same lineage, and osteoblasts fuse together to form osteoclasts. Osteoclast_sentence_38

After years of controversy it is now clear that these cells develop from the self fusion of macrophages. Osteoclast_sentence_39

It was in the beginning of 1980 that the monocyte phagocytic system was recognized as precursor of osteoclasts. Osteoclast_sentence_40

Osteoclast formation requires the presence of RANKL (receptor activator of nuclear factor κβ ligand) and M-CSF (Macrophage colony-stimulating factor). Osteoclast_sentence_41

These membrane-bound proteins are produced by neighbouring stromal cells and osteoblasts, thus requiring direct contact between these cells and osteoclast precursors. Osteoclast_sentence_42

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. Osteoclast_sentence_43

Both of these molecules are necessary for osteoclastogenesis and are widely involved in the differentiation of monocyte/macrophage derived cells. Osteoclast_sentence_44

RANKL is a member of the tumour necrosis family (TNF), and is essential in osteoclastogenesis. Osteoclast_sentence_45

RANKL knockout mice exhibit a phenotype of osteopetrosis and defects of tooth eruption, along with an absence or deficiency of osteoclasts. Osteoclast_sentence_46

RANKL activates NF-κβ (nuclear factor-κβ) and NFATc1 (nuclear factor of activated t cells, cytoplasmic, calcineurin-dependent 1) through RANK. Osteoclast_sentence_47

NF-κβ activation is stimulated almost immediately after RANKL-RANK interaction occurs and is not upregulated. Osteoclast_sentence_48

NFATc1 stimulation, however, begins ~24–48 hours after binding occurs and its expression has been shown to be RANKL dependent. Osteoclast_sentence_49

Osteoclast differentiation is inhibited by osteoprotegerin (OPG), which is produced by osteoblasts and binds to RANKL thereby preventing interaction with RANK. Osteoclast_sentence_50

It may be important to note that while osteoclasts are derived from the hematopoietic lineage, osteoblasts are derived from mesenchymal stem cells. Osteoclast_sentence_51

Function Osteoclast_section_3

Once activated, osteoclasts move to areas of microfracture in the bone by chemotaxis. Osteoclast_sentence_52

Osteoclasts lie in small cavities called Howship's lacunae, formed from the digestion of the underlying bone. Osteoclast_sentence_53

The sealing zone is the attachment of the osteoclast's plasma membrane to the underlying bone. Osteoclast_sentence_54

Sealing zones are bounded by belts of specialized adhesion structures called podosomes. Osteoclast_sentence_55

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. Osteoclast_sentence_56

The osteoclast releases hydrogen ions through the action of carbonic anhydrase (H2O + CO2HCO3 + H) through the ruffled border into the resorptive cavity, acidifying and aiding dissolution of the mineralized bone matrix into Ca, H3PO4, H2CO3, water and other substances. Osteoclast_sentence_57

Dysfunction of the carbonic anhydrase has been documented to cause some forms of osteopetrosis. Osteoclast_sentence_58

Hydrogen ions are pumped against a high concentration gradient by proton pumps, specifically a unique vacuolar-ATPase. Osteoclast_sentence_59

This enzyme has been targeted in the prevention of osteoporosis. Osteoclast_sentence_60

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. Osteoclast_sentence_61

These enzymes are released into the compartment by lysosomes. Osteoclast_sentence_62

Of these hydrolytic enzymes, cathepsin K is of most importance. Osteoclast_sentence_63

Cathepsin K and other cathepsins Osteoclast_section_4

Cathepsin K is a collagenolytic, papain-like, cysteine protease that is mainly expressed in osteoclasts, and is secreted into the resorptive pit. Osteoclast_sentence_64

Cathepsin K is the major protease involved in the degradation of type I collagen and other noncollagenous proteins. Osteoclast_sentence_65

Mutations in the cathepsin K gene are associated with pycnodysostosis, a hereditary osteopetrotic disease, characterised by a lack of functional cathepsin K expression. Osteoclast_sentence_66

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. Osteoclast_sentence_67

Cathepsin K has an optimal enzymatic activity in acidic conditions. Osteoclast_sentence_68

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. Osteoclast_sentence_69

Upon polarization of the osteoclast over the site of resorption, cathepsin K is secreted from the ruffled border into the resorptive pit. Osteoclast_sentence_70

Cathepsin K transmigrates across the ruffled border by intercellular vesicles and is then released by the functional secretory domain. Osteoclast_sentence_71

Within these intercellular vesicles, cathepsin K, along with reactive oxygen species generated by TRAP, further degrades the bone extracellular matrix. Osteoclast_sentence_72

Several other cathepsins are expressed in osteoclasts including cathepsins B, C, D, E, G, and L. The function of these cysteine and aspartic proteases is generally unknown within bone, and they are expressed at much lower levels than cathepsin K. Osteoclast_sentence_73

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. Osteoclast_sentence_74

Matrix metalloproteinases Osteoclast_section_5

The matrix metalloproteinases (MMPs) comprise a family of more than 20 zinc-dependent endopeptidases. Osteoclast_sentence_75

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. Osteoclast_sentence_76

MMP9 is associated with the bone microenvironment. Osteoclast_sentence_77

It is expressed by osteoclasts, and is known to be required for osteoclast migration and is a powerful gelatinase. Osteoclast_sentence_78

Transgenic mice lacking MMP-9 develop defects in bone development, intraosseous angiogenesis, and fracture repair. Osteoclast_sentence_79

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. Osteoclast_sentence_80

MMPs expressed by the osteoclast include MMP-9, -10, -12, and -14. apart from MMP-9, little is known about their relevance to the osteoclast, however, high levels of MMP-14 are found at the sealing zone. Osteoclast_sentence_81

Osteoclast physiology Osteoclast_section_6

In the 1980s and 90s the physiology of typical osteoclasts was studied in detail. Osteoclast_sentence_82

With the isolation of the ruffled border, ion transport across it was studied directly in biochemical detail. Osteoclast_sentence_83

Energy-dependent acid transport was verified and the postulated proton pump purified. Osteoclast_sentence_84

With the successful culture of osteoclasts, it became apparent that they are organized to support the massive transport of protons for acidification of the resorption compartment and solubilization of the bone mineral. Osteoclast_sentence_85

This includes ruffled border Cl permeability to control membrane potential and basolateral Cl/HCO3 exchange to maintain cytosolic pH in physiologically acceptable ranges.> Osteoclast_sentence_86

The effectiveness of its ion secretion depends upon the osteoclast forming an effective seal around the resorption compartment. Osteoclast_sentence_87

The positioning of this "sealing zone" appears to be mediated by integrins expressed on the osteoclast surface. Osteoclast_sentence_88

With the sealing zone in place, the multinucleated osteoclast reorganizes itself. Osteoclast_sentence_89

Developing the highly invaginated ruffled membrane apposing the resorption compartment allows massive secretory activity. Osteoclast_sentence_90

In addition, it permits the vesicular transcytosis of the mineral and degraded collagen from the ruffled border to the free membrane of the cell, and its release into the extracellular compartment. Osteoclast_sentence_91

This activity completes the bone resorption, and both the mineral components and collagen fragments are released to the general circulation. Osteoclast_sentence_92

Regulation Osteoclast_section_7

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). Osteoclast_sentence_93

This last hormone, IL-6, is one of the factors in the disease osteoporosis, which is an imbalance between bone resorption and bone formation. Osteoclast_sentence_94

Osteoclast activity is also mediated by the interaction of two molecules produced by osteoblasts, namely osteoprotegerin and RANK ligand. Osteoclast_sentence_95

Note that these molecules also regulate differentiation of the osteoclast. Osteoclast_sentence_96

Odontoclast Osteoclast_section_8

An odontoclast (/odon·to·clast/; o-don´to-klast) is an osteoclast associated with absorption of the roots of deciduous teeth. Osteoclast_sentence_97

Alternate use of term Osteoclast_section_9

An osteoclast can also be an instrument used to fracture and reset bones (the origin is Greek osteon: bone and klastos: broken). Osteoclast_sentence_98

To avoid confusion, the cell was originally termed osotoclast. Osteoclast_sentence_99

When the surgical instrument went out of use, the cell became known by its present name. Osteoclast_sentence_100

Clinical significance Osteoclast_section_10

Giant osteoclasts can occur in some diseases, including Paget's disease of bone and bisphosphonate toxicity. Osteoclast_sentence_101

In cats, abnormal odontoclast activity can cause feline odontoclastic resorptive lesions, necessitating extraction of the affected teeth. Osteoclast_sentence_102

History Osteoclast_section_11

Osteoclasts were discovered by Kolliker in 1873. Osteoclast_sentence_103

See also Osteoclast_section_12


Credits to the contents of this page go to the authors of the corresponding Wikipedia page: en.wikipedia.org/wiki/Osteoclast.