| Osteoclast | |
|---|---|
 Light micrograph of an osteoclast displaying typical distinguishing characteristics: a large cell with multiple nuclei and a "foamy" cytosol. | |
 Illustration showing a single osteoclast | |
| Details | |
| Precursor | osteoclast progenitors |
| Location | Bone |
| Function | Removal ofbone tissue |
| Identifiers | |
| Latin | osteoclastus |
| MeSH | D010010 |
| TH | H2.00.03.7.00005 |
| FMA | 66781 |
| Anatomical terms of microanatomy | |
Anosteoclast (from Ancient Greek ὀστέον (osteon) 'bone' and κλαστός (clastos) 'broken') is a type ofbone cell that removesbone tissue. This function is critical in the maintenance, repair, andremodeling ofbones of thevertebralskeleton. The osteoclast disassembles and digests the composite of hydrated protein andmineral at a molecular level by secreting acid and acollagenase, a process known asbone resorption. This process also helps regulate the level of bloodcalcium.
Osteoclasts are found on those surfaces of bone that are undergoing resorption. On such surfaces, the osteoclasts are seen to be located in shallow depressions calledresorption bays (Howship's lacunae). The resorption bays are created by the erosive action of osteoclasts on the underlying bone. The border of the lower part of an osteoclast exhibits finger-like processes due to the presence of deep infoldings of thecell membrane; this border is calledruffled border. The ruffled border lies in contact with the bone surface within a resorption bay. The periphery of the ruffled border is surrounded by a ring-like zone ofcytoplasm, which is devoid of cellorganelles but rich inactin filaments. This zone is called theclear zone orsealing zone. The actin filaments enable the cell membrane surrounding the sealing zone to be anchored firmly to the bony wall of Howship's lacunae. In this way, a closed subosteoclastic compartment is created between the ruffled border and the bone that is undergoing resorption. The osteoclasts secretehydrogen ions,collagenase,cathepsin K and hydrolytic enzymes into this compartment. 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. The osteoclasts pump hydrogen ions into the 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. After the removal of minerals, collagenase and gelatinase are secreted into the subosteoclastic compartment. These enzymes digest and degrade collagen and other organic components of decalcified bone matrix. The degradation products are phagocytosed by osteoclasts at the ruffled border. Because of their phagocytic properties, osteoclasts are considered to be a component of themononuclear phagocyte system (MPS). The activity of osteoclasts is controlled by hormones and cytokines. Calcitonin, a hormone of the thyroid gland, suppresses osteoclastic activity. Osteoclasts do not have receptors for parathyroid hormone (PTH). However, PTH stimulatesosteoblasts to secrete a cytokine called osteoclast-stimulating factor, which is a potent stimulator of osteoclastic activity.[1]
An odontoclast (/odon·to·clast/; o-don´to-klast) is an osteoclast associated with the absorption of the roots ofdeciduous teeth.[2][3][4]
An osteoclast is a largemultinucleated cell and human osteoclasts on bone typically have four nuclei[5] and are 150–200 μm in diameter. When osteoclast-inducing cytokines are used to convertmacrophages to osteoclasts, very large cells that may reach 100 μm in diameter occur. 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.[6][7] 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.
In bone, osteoclasts are found in pits in the bone surface which are called resorption bays, orHowship'slacunae. Osteoclasts are characterized by a cytoplasm with a homogeneous, "foamy" appearance. This appearance is due to a high concentration ofvesicles andvacuoles. These vacuoles includelysosomes filled withacid phosphatase. This permits characterization of osteoclasts by their staining for highexpression oftartrate resistant acid phosphatase (TRAP) andcathepsin K. Osteoclast rough endoplasmic reticulum is sparse, and the Golgi complex is extensive.[8][9][10]
At a site of active bone resorption, the osteoclast forms a specializedcell membrane, the "ruffled border", that opposes the surface of the bone tissue. 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.
Since their discovery in 1873 there has been considerable debate about their origin. Three theories were dominant: from 1949 to 1970 the connective tissue origin was popular, which stated that osteoclasts andosteoblasts are of the same lineage, and osteoblasts fuse together to form osteoclasts. After years of controversy it is now clear that these cells develop from the self fusion of macrophages.[11] It was in the beginning of 1980 that themonocyte phagocytic system was recognized as precursor of osteoclasts.[12] Osteoclast formation requires the presence ofRANKL (receptor activator of nuclear factor κβ ligand) andM-CSF (Macrophage colony-stimulating factor). These membrane-bound proteins are produced by neighbouringstromal cells andosteoblasts, thus requiring direct contact between these cells and osteoclastprecursors.
M-CSF acts through its receptor on the osteoclast, c-fms (colony-stimulating factor 1 receptor), a transmembranetyrosine kinase-receptor, leading tosecondary messenger activation of tyrosine kinase Src. Both of these molecules are necessary for osteoclastogenesis and are widely involved in thedifferentiation of monocyte/macrophage derived cells.
RANKL is a member of the tumour necrosis family (TNF), and is essential in osteoclastogenesis. RANKL knockout mice exhibit a phenotype ofosteopetrosis and defects of tooth eruption, along with an absence or deficiency of osteoclasts. RANKL activates NF-κβ (nuclear factor-κβ) and NFATc1 (nuclear factor of activated t cells, cytoplasmic, calcineurin-dependent 1) throughRANK. 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 byosteoprotegerin (OPG), which is produced by osteoblasts and binds to RANKL thereby preventing interaction with RANK. While osteoclasts are derived from the hematopoietic lineage, osteoblasts are derived from mesenchymal stem cells.[13][14]
Once activated, osteoclasts move to areas of microfracture in the bone bychemotaxis. Osteoclasts lie in small cavities called Howship's lacunae, formed from the digestion of the underlying bone. The sealing zone is the attachment of the osteoclast'splasma membrane to the underlying bone. Sealing zones are bounded by belts of specialized adhesion structures calledpodosomes. Attachment to the bone matrix is facilitated by integrin receptors, such as αvβ3, via the specificamino acid motif Arg-Gly-Asp in bone matrix proteins, such asosteopontin. The osteoclast releases hydrogen ions through the action ofcarbonic anhydrase (H2O +CO2 →HCO3− +H+) through theruffled border into the resorptive cavity, acidifying and aiding dissolution of the mineralized bonematrix intoCa2+, H3PO4, H2CO3, water and other substances. Dysfunction of the carbonic anhydrase has been documented to cause some forms of osteopetrosis. Hydrogen ions are pumped against a high concentration gradient byproton pumps, specifically a uniquevacuolar-ATPase. This enzyme has been targeted in the prevention ofosteoporosis. In addition, severalhydrolytic enzymes, such as members of thecathepsin and matrix metalloprotease (MMP) groups, are released to digest the organic components of the matrix. These enzymes are released into the compartment bylysosomes. Of these hydrolytic enzymes, cathepsin K is of most importance.
Cathepsin K is a collagenolyticpapain-likecysteine protease that is mainly expressed in osteoclasts, and is secreted into the resorptive pit. Cathepsin K is the majorprotease involved in the degradation of type I collagen and other noncollagenous proteins. Mutations in the cathepsin K gene are associated withpycnodysostosis, a hereditaryosteopetrotic disease, characterised by a lack of functional cathepsin K expression. 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.
Upon polarization of the osteoclast over the site of resorption, cathepsin K is secreted from the ruffled border into the resorptive pit. Cathepsin K transmigrates across the ruffled border by intercellular vesicles and is then released by the functionalsecretory domain. Within these intercellular vesicles, cathepsin K, along withreactive oxygen species generated byTRAP, further degrades the bone extracellular matrix.
Several other cathepsins are expressed in osteoclasts includingcathepsins B,C,D,E,G, andL. The function of thesecysteine andaspartic proteases is generally unknown within bone, and they are expressed at much lower levels than cathepsin K.
Studies on cathepsin Lknockout mice have been mixed, with a report of reducedtrabecular bone inhomozygous andheterozygous cathepsin L knockout mice compared to wild-type and another report finding no skeletal abnormalities.
Thematrix metalloproteinases (MMPs) comprise a family of more than 20 zinc-dependent endopeptidases. 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 ofgrowth factors and are required for tumor metastasis and angiogenesis.
MMP9 is associated with the bone microenvironment. It is expressed by osteoclasts, and is known to be required for osteoclastmigration and is a powerful gelatinase. Transgenic mice lacking MMP-9 develop defects in bone development, intraosseousangiogenesis, and fracture repair.
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 known about their relevance to the osteoclast, however, high levels of MMP-14 are found at the sealing zone.
In the 1980s and 90s the physiology of typical osteoclasts was studied in detail. With the isolation of the ruffled border, ion transport across it was studied directly in biochemical detail. Energy-dependent acid transport was verified and the postulated proton pump purified.[15][16] 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. This includes ruffled border Cl− permeability to control membrane potential and basolateral Cl−/HCO3− exchange to maintain cytosolic pH in physiologically acceptable ranges.[17][18][19]
The effectiveness of its ion secretion depends upon the osteoclast forming an effective seal around the resorption compartment. The positioning of this "sealing zone" appears to be mediated by integrins expressed on the osteoclast surface.[20] With the sealing zone in place, the multinucleated osteoclast reorganizes itself. Developing the highly invaginated ruffled membrane apposing the resorption compartment allows massive secretory activity. In addition, it permits the vesiculartranscytosis of the mineral and degraded collagen from the ruffled border to the free membrane of the cell, and its release into the extracellular compartment.[21][22] This activity completes the bone resorption, and both the mineral components and collagen fragments are released to the general circulation.
Osteoclasts are regulated by severalhormones, includingparathyroid hormone (PTH) from the parathyroid gland,calcitonin from the thyroid gland, andgrowth factor interleukin 6 (IL-6). This last hormone,IL-6, is one of the factors in the diseaseosteoporosis. Osteoporosis occurs when there is an imbalance between the bone resorption activities of osteoclasts and the bone formation activities of osteoblasts.[23]
Osteoclast activity is also mediated by the interaction of two molecules produced by osteoblasts, namelyosteoprotegerin andRANK ligand. These molecules also regulate differentiation of the osteoclast.[24][25]
Anodontoclast is an osteoclast associated withabsorption of the roots ofdeciduous teeth.[2][3][4]
An osteoclast can also be an instrument used to fracture and reset bones (the origin is Greekosteon: bone andklastos: 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.
Giant osteoclasts can occur in some diseases, includingPaget's disease of bone andbisphosphonate toxicity.
In cats, abnormal odontoclast activity can causefeline odontoclastic resorptive lesions, necessitating extraction of the affected teeth.
Osteoclasts play a major role in orthodontic tooth movement and pathologic migration of periodontally compromised teeth.
Osteoclasts were discovered byKölliker in 1873.[12]
| International | |
|---|---|
| National | |
| Other | |
