An osteoclast and “broken” (κλαστός)) is a type of bone cell that resorbs boney tissue. This function is critical in the maintenance and repair of compact skeletal bones in the mammalian skeleton. These bones are stronger than aluminum on a weight basis by being a composite material of approximately equal amounts of hydrated protein and mineral. The osteoclast disassembles this very strong composite at a molecular level by secreting acid and a collagenase. This process is known as bone resorption. Osteoclasts and osteoblasts are instrumental in controlling the amount of bone tissue: osteoblasts form bone, osteoclasts resorb bone.
In bone, osteoclasts are found in pits in the bone surface which are called resorption bays, or Howship’s Lacunae. Osteoclasts are characterized by a cytoplasm with a homogeneous, “foamy” appearance. This appearance is due to a high concentration of vesicles and vacuoles. These vacuoles include lysosomes filled with acid phophatase. This permits characterization of Osteoclasts by their staining for high expression of tartrate resistant acid phosphatase and cathepsin K. Osteoclast rough endoplasmic reticulum is sparse, and the Golgi complex is extensive.
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. 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.
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 and in biochemical detail. Energy dependent acid transport verified and the postulated proton pump purified. With the successful culture of these osteoclasts it quickly became apparent that the this cell was 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. These observations make it abundantly clear that the typical osteoclast is optimized to secrete sufficient acid to sustain bone mineral solubilization. The effectiveness of this optimized secretion depends upon the osteoclast forming and effective seal around the resorption compartment. The positioning of this “sealing zone” appears to be mediated by integrins expressed on the osteoclast surface. With the sealing zone in place the multinucleated osteoclast reorganizes itself. Developing the highly invaginated ruffled membrane apposing the resorption compartment allows the massive secretory active described above. 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 release into the extracellular compartment. This activity completes the bone resorption and both the mineral components and collagen fragments are released to the general circulation.
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 and osteoblasts are of the same lineage, and ostoblasts fuse together to form osteoclasts.After years of controversy it is now clear that these cells develop from the self fusion of macrophages. It was in the beginning of 1980 that the monocyte phagocytic system was recognized as precursor of osteoclasts. Osteoclast formation requires the presence of RANKL and M-CSF (Macrophage colony-stimulating factor). These membrane bound proteins are produced by neighbouring stromal cells and osteoblasts, thus requiring direct contact between these cells and osteoclast precursors.
M-CSF acts through its receptor on the osteoclast, c-fms, a transmembrane tyrosine kinase-receptor, leading to secondary messenger activation of tyrosine kinase Src. Both of these molecules are necessary for osteoclastogenesis and are widely involved in the differentiation of monocyte/macrophage derived cells.
Osteoclast differentiation is inhibited by osteoprotegerin, which is produced by osteoblasts and binds to RANKL thereby preventing interaction with RANK.
Once activated, osteoclasts move to areas of microfracture in the bone by chemotaxis. Osteoclasts lie in a small cavity called Howship’s lacunae, formed from the digestion of the underlying bone. The sealing zone is the attachment of the osteoclast’s plasma membrane to the underlying bone. Sealing zones are bounded by belts of specialized adhesion structures called podosomes. 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. The osteoclast releases hydrogen ions through the action of carbonic anhydrase through the ruffled border into the resorptive cavity, acidifying and aiding dissolution of the mineralized bone matrix into Ca2+, 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 by proton pumps, specifically a unique vacuolar-ATPase. This enzyme has been targeted in the prevention of osteoporosis. 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. These enzymes are released into the compartment by lysosomes. Of these hydrolytic enzymes, cathepsin K is of most importance.
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 functional secretory domain. Within these intercellular vesicles, cathepsin K, along with reactive oxygen species generated by TRAP, further degrades the bone extracellular matrix.
Numerous other cathepsins are expressed in osteoclasts. These include cathepsin 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.
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.
The matrix metalloproteinases comprise a family of more than 20 zinc-dependent endopeptidases. The role of matrix metalloproteinases 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.
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. Transgenic mice lacking MMP-9 develop defects in bone development, intraosseous angiogenesis, 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.
Osteoclasts are regulated by several hormones, including parathyroid hormone from the parathyroid gland, calcitonin from the thyroid gland, and growth factor interleukin 6 (IL-6). 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 activity is also mediated by the interaction of two molecules produced by osteoblasts, namely osteoprotegerin and RANK ligand. Note that these molecules also regulate differentiation of the osteoclast.
An osteoclast can also be an instrument used to fracture and reset bones. 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.
Related Sites for Osteoclast
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- Osteoclast differentiation and activation. read Osteoclast