Osteoclast
Encyclopedia
An osteoclast is a type of bone cell
that removes bone tissue by removing its mineralized matrix and breaking up the organic bone (organic dry weight is 90% collagen). This process is known as bone resorption
. Osteoclasts were discovered by Kolliker in 1873. Osteoclasts and osteoblast
s are instrumental in controlling the amount of bone tissue: osteoblasts form bone, osteoclasts resorb bone. Osteoclasts are formed by the fusion of cells of the monocyte
-macrophage
cell line. Osteoclasts are characterized by high expression
of tartrate resistant acid phosphatase
(TRAP) and cathepsin K
.
An osteoclast is a large cell that is 40 micrometer in diameter. It contains 15-20 closely packed oval-shaped nuclei. 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 are lysosomes filled with acid phophatase. Osteoclast rough endoplasmic reticulum is sparse, and the Golgi complex is extensive.
ligand (receptor activator of nuclear factor κβ) 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 (colony-stimulating factor 1 receptor), 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.
RANKL
is a member of the tumour necrosis family (TNF
), and is essential in osteoclastogenesis. RANKL knockout mice exhibit a phenotype of osteopetrosis
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) through RANK
. 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 is produced by osteoblasts and binds to RANKL thereby preventing interaction with RANK.
. 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 plasmalemma
to the underlying bone
. Sealing zones are bounded by belts of specialized adhesion structures called podosome
s. 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 ion
s through the action of carbonic anhydrase (H2O + CO2
→ HCO3
- + H
+) 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 pump
s, 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 lysosome
s. Of these hydrolytic enzymes, cathepsin K
is of most importance.
is a collagenolytic, papain
-like, cysteine protease that is mainly expressed in osteoclasts, and is secreted into the resorptive pit. Mutations in the cathepsin K gene are associated with pycnodysostosis, a hereditary osteopetrotic
disease, characterised by 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.
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. 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.
Numerous other cathepsin
s 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.
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.
(PTH) 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.
Bone cell
There are five types of bone cells.*Osteoblasts - These are commonly called bone-forming cells. They secrete osteoid, which forms the bone matrix. They also begin mieralization, and are unable to divide....
that removes bone tissue by removing its mineralized matrix and breaking up the organic bone (organic dry weight is 90% collagen). This process is known as bone resorption
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 were discovered by Kolliker in 1873. Osteoclasts and osteoblast
Osteoblast
Osteoblasts are mononucleate cells that are responsible for bone formation; in essence, osteoblasts are specialized fibroblasts that in addition to fibroblastic products, express bone sialoprotein and osteocalcin.Osteoblasts produce a matrix of osteoid, which is composed mainly of Type I collagen...
s are instrumental in controlling the amount of bone tissue: osteoblasts form bone, osteoclasts resorb bone. Osteoclasts are formed by the fusion of cells of the monocyte
Monocyte
Monocytes are a type of white blood cell and are part of the innate immune system of vertebrates including all mammals , birds, reptiles, and fish. Monocytes play multiple roles in immune function...
-macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
cell line. Osteoclasts are characterized by high expression
Protein expression
Protein expression is a subcomponent of gene expression. It consists of the stages after DNA has been translated into polypeptide chains, which are ultimately folded into proteins...
of tartrate resistant acid phosphatase
Tartrate resistant acid phosphatase
Tartrate-resistant acid phosphatase or acid phosphatase 5, tartrate resistant is a glycosylated monomeric metalloenzyme expressed in mammals. It has a molecular weight of approximately 35kDa, a basic isoelectric point , and optimal activity in acidic conditions. TRAP is synthesized as latent...
(TRAP) and cathepsin K
Cathepsin K
Cathepsin K, abbreviated CTSK, is an enzyme which in humans is encoded by the CTSK gene.- Function :The protein encoded by this gene is a lysosomal cysteine protease involved in bone remodeling and resorption...
.
Morphology
John Howship
John Howship was an English surgeon remembered for describing the Howship-Romberg sign. He was an assistant surgeon at St. George's Infirmary, London and lecturer at St. George's Hospital Medical School. He was a member of the council of the Royal College of Surgeons at the time of his death from...
Lacunae. Osteoclasts are characterized by a cytoplasm with a homogeneous, "foamy" appearance. This appearance is due to a high concentration of vesicles
Vesicle (biology)
A vesicle is a bubble of liquid within another liquid, a supramolecular assembly made up of many different molecules. More technically, a vesicle is a small membrane-enclosed sack that can store or transport substances. Vesicles can form naturally because of the properties of lipid membranes , or...
and vacuoles. These vacuoles are lysosomes filled with acid phophatase. 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 membraneCell membraneThe cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
, the "ruffled border," that touches the surface of the bone tissue. 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 calciumCalciumCalcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
and phosphatePhosphateA phosphate, an inorganic chemical, is a salt of phosphoric acid. In organic chemistry, a phosphate, or organophosphate, is an ester of phosphoric acid. Organic phosphates are important in biochemistry and biogeochemistry or ecology. Inorganic phosphates are mined to obtain phosphorus for use in...
ions. These ions are absorbed into small vesicleVesicle (biology)A vesicle is a bubble of liquid within another liquid, a supramolecular assembly made up of many different molecules. More technically, a vesicle is a small membrane-enclosed sack that can store or transport substances. Vesicles can form naturally because of the properties of lipid membranes , or...
s (see endocytosisEndocytosisEndocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...
), which move across the cell and eventually are released into the extracellular fluidExtracellular fluidExtracellular fluid usually denotes all body fluid outside of cells. The remainder is called intracellular fluid.In some animals, including mammals, the extracellular fluid can be divided into two major subcompartments, interstitial fluid and blood plasma...
, thus increasing levels of the ions in the blood.
Origin
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. At certain times osteoclasts dissociate into osteoblasts, which finally form osteocytes. In the 1970s the biphyletic theory became popular; it states that osteoblasts and osteoclasts are of different lineage. It was in the beginning of 1980 that the monocyte phagocytic system was recognized as precursor of osteoclasts. Osteoclast formation requires the presence of RANKRANK
Receptor Activator of Nuclear Factor κ B , also known as TRANCE Receptor, is a type I membrane protein that is expressed on the surface of osteoclasts and is involved in their activation upon ligand binding...
ligand (receptor activator of nuclear factor κβ) and M-CSF (Macrophage colony-stimulating factor)
Macrophage colony-stimulating factor
Macrophage colony-stimulating factor, or M-CSF, is a secreted cytokine which influences hematopoietic stem cells to differentiate into macrophages or other related cell types. Eukaryotic cells also produce M-CSF in order to combat intercellular viral infection. M-CSF binds to the Colony...
. 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 (colony-stimulating factor 1 receptor), a transmembrane tyrosine kinase
Tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....
-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.
RANKL
RANKL
Receptor activator of nuclear factor kappa-B ligand , also known as tumor necrosis factor ligand superfamily member 11 , TNF-related activation-induced cytokine , osteoprotegerin ligand , and osteoclast differentiation factor , is a protein that in humans is encoded by the TNFSF11 gene.RANKL is...
is a member of the tumour necrosis family (TNF
Tumor necrosis factors
Tumor necrosis factors refers to a group of cytokines family that can cause cell death . The first two members of the family to be identified were:...
), and is essential in osteoclastogenesis. RANKL knockout mice exhibit a phenotype of osteopetrosis
Osteopetrosis
Osteopetrosis, literally "stone bone", also known as marble bone disease and Albers-Schonberg disease is an extremely rare inherited disorder whereby the bones harden, becoming denser, in contrast to more prevalent conditions like osteoporosis, in which the bones become less dense and more brittle,...
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) through RANK
RANK
Receptor Activator of Nuclear Factor κ B , also known as TRANCE Receptor, is a type I membrane protein that is expressed on the surface of osteoclasts and is involved in their activation upon ligand binding...
. 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
Osteoprotegerin
Osteoprotegerin , also known as osteoclastogenesis inhibitory factor , or tumor necrosis factor receptor superfamily member 11B , is a protein that in humans is encoded by the TNFRSF11B gene...
(OPG), which is produced by osteoblasts and binds to RANKL thereby preventing interaction with RANK.
Function
Once activated, osteoclasts move to areas of microfracture in the bone by chemotaxisChemotaxis
Chemotaxis is the phenomenon in which somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemicals in their environment. This is important for bacteria to find food by swimming towards the highest concentration of food molecules,...
. 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 plasmalemma
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
to the underlying bone
Bone
Bones are rigid organs that constitute part of the endoskeleton of vertebrates. They support, and protect the various organs of the body, produce red and white blood cells and store minerals. Bone tissue is a type of dense connective tissue...
. Sealing zones are bounded by belts of specialized adhesion structures called podosome
Podosome
Podosomes are small cylindrical ECM adhesion structures approximately 0.5 um in diameter. They contain focal contact proteins like vinculin and paxillin and are found primarily in malignant cells. They can also be found in normal cells such as macrophages and osteoclasts...
s. 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
Osteopontin
Osteopontin , also known as bone sialoprotein I , early T-lymphocyte activation , secreted phosphoprotein 1 , 2ar and Rickettsia resistance , is a human gene product, which is also conserved in other species...
. The osteoclast releases hydrogen ion
Hydrogen ion
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, two different classes can be distinguished: positively charged ions and negatively charged ions....
s through the action of carbonic anhydrase (H2O + CO2
Carbon dioxide
Carbon dioxide is a naturally occurring chemical compound composed of two oxygen atoms covalently bonded to a single carbon atom...
→ HCO3
Bicarbonate
In inorganic chemistry, bicarbonate is an intermediate form in the deprotonation of carbonic acid...
- + H
Hydrogen ion
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, two different classes can be distinguished: positively charged ions and negatively charged ions....
+) through the ruffled border into the resorptive cavity, acidifying and aiding dissolution of the mineralized bone
Bone
Bones are rigid organs that constitute part of the endoskeleton of vertebrates. They support, and protect the various organs of the body, produce red and white blood cells and store minerals. Bone tissue is a type of dense connective tissue...
matrix
Matrix (biology)
In biology, matrix is the material between animal or plant cells, in which more specialized structures are embedded, and a specific part of the mitochondrion that is the site of oxidation of organic molecules. The internal structure of connective tissues is an extracellular matrix...
into Ca2+
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
, H3PO4, H2CO3, water and other substances. Dysfunction of the carbonic anhydrase has been documented to cause some forms of osteopetrosis
Osteopetrosis
Osteopetrosis, literally "stone bone", also known as marble bone disease and Albers-Schonberg disease is an extremely rare inherited disorder whereby the bones harden, becoming denser, in contrast to more prevalent conditions like osteoporosis, in which the bones become less dense and more brittle,...
. Hydrogen ions are pumped against a high concentration gradient by proton pump
Proton pump
A proton pump is an integral membrane protein that is capable of moving protons across a cell membrane, mitochondrion, or other organelle. Mechanisms are based on conformational changes of the protein structure or on the Q cycle.-Function:...
s, specifically a unique vacuolar-ATPase
ATPase
ATPases are a class of enzymes that catalyze the decomposition of adenosine triphosphate into adenosine diphosphate and a free phosphate ion. This dephosphorylation reaction releases energy, which the enzyme harnesses to drive other chemical reactions that would not otherwise occur...
. This enzyme has been targeted in the prevention of osteoporosis
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
. In addition, several hydrolytic enzymes, such as members of the cathepsin
Cathepsin
Cathepsins are proteases: proteins that break apart other proteins, found in many types of cells including those in all animals. There are approximately a dozen members of this family, which are distinguished by their structure, catalytic mechanism, and which proteins they cleave...
and matrix metalloprotease(MMP) groups , are released to digest the organic components of the matrix
Matrix (biology)
In biology, matrix is the material between animal or plant cells, in which more specialized structures are embedded, and a specific part of the mitochondrion that is the site of oxidation of organic molecules. The internal structure of connective tissues is an extracellular matrix...
. These enzymes are released into the compartment by lysosome
Lysosome
thumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s: [[nucleoli]] [[cell nucleus|nucleus]] [[ribosomes]] [[vesicle |vesicle]] rough [[endoplasmic reticulum]]...
s. Of these hydrolytic enzymes, cathepsin K
Cathepsin K
Cathepsin K, abbreviated CTSK, is an enzyme which in humans is encoded by the CTSK gene.- Function :The protein encoded by this gene is a lysosomal cysteine protease involved in bone remodeling and resorption...
is of most importance.
Cathepsin K and other cathepsins
Cathepsin KCathepsin K
Cathepsin K, abbreviated CTSK, is an enzyme which in humans is encoded by the CTSK gene.- Function :The protein encoded by this gene is a lysosomal cysteine protease involved in bone remodeling and resorption...
is a collagenolytic, papain
Papain
Papain, also known as papaya proteinase I, is a cysteine protease enzyme present in papaya and mountain papaya .-Papain family:...
-like, cysteine protease that is mainly expressed in osteoclasts, and is secreted into the resorptive pit. Mutations in the cathepsin K gene are associated with pycnodysostosis, a hereditary osteopetrotic
Osteopetrosis
Osteopetrosis, literally "stone bone", also known as marble bone disease and Albers-Schonberg disease is an extremely rare inherited disorder whereby the bones harden, becoming denser, in contrast to more prevalent conditions like osteoporosis, in which the bones become less dense and more brittle,...
disease, characterised by 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.
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
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
involved in the degradation of type I collagen and other noncollagenous proteins, which have been demineralized by the acidic environment of the resorptive pit. 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
Reactive oxygen species
Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....
by TRAP
Tartrate resistant acid phosphatase
Tartrate-resistant acid phosphatase or acid phosphatase 5, tartrate resistant is a glycosylated monomeric metalloenzyme expressed in mammals. It has a molecular weight of approximately 35kDa, a basic isoelectric point , and optimal activity in acidic conditions. TRAP is synthesized as latent...
further degrades bone resorption products.
Numerous other cathepsin
Cathepsin
Cathepsins are proteases: proteins that break apart other proteins, found in many types of cells including those in all animals. There are approximately a dozen members of this family, which are distinguished by their structure, catalytic mechanism, and which proteins they cleave...
s are expressed in osteoclasts. These include cathepsin B
Cathepsin B
Cathepsin B is an enzymatic protein belonging to the peptidase families. In humans, it is coded by the CTSB gene.- Function :...
, C
Cathepsin C
Cathepsin C also known as dipeptidyl peptidase I is a lysosomal exo-cysteine protease belonging to the peptidase C1 family...
, D, E, G, and L. The function of these cysteine
Cysteine protease
Proteases are enzymes that degrade polypeptides. Cysteine proteases have a common catalytic mechanism that involves a nucleophilic cysteine thiol in a catalytic dyad. The first step is deprotonation of a thiol in the enzyme's active site by an adjacent amino acid with a basic side chain, usually a...
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.
Matrix metalloproteinases
The matrix 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 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
Cell migration
Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound healing and immune responses all require the orchestrated movement of cells in particular directions to specific locations...
and is a powerful gelatinase. Transgenic mice lacking MMP-9 develop defects in bone development, intraosseous angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
, 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.
Regulation
Osteoclasts are regulated by several hormones, including parathyroid hormoneParathyroid hormone
Parathyroid hormone , parathormone or parathyrin, is secreted by the chief cells of the parathyroid glands as a polypeptide containing 84 amino acids...
(PTH) from the parathyroid gland, calcitonin
Calcitonin
Calcitonin is a 32-amino acid linear polypeptide hormone that is producedin humans primarily by the parafollicular cells of the thyroid, and in many other animals in the ultimobranchial body. It acts to reduce blood calcium , opposing the effects of parathyroid hormone . Calcitonin has been found...
from the thyroid gland, and growth factor interleukin 6
Interleukin
Interleukins are a group of cytokines that were first seen to be expressed by white blood cells . The term interleukin derives from "as a means of communication", and "deriving from the fact that many of these proteins are produced by leukocytes and act on leukocytes"...
(IL-6). This last hormone, IL-6
Interleukin 6
Interleukin-6 is a protein that in humans is encoded by the IL6 gene.IL-6 is an interleukin that acts as both a pro-inflammatory and anti-inflammatory cytokine. It is secreted by T cells and macrophages to stimulate immune response, e.g. during infection and after trauma, especially burns or other...
, is one of the factors in the disease osteoporosis
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
, 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
Osteoprotegerin
Osteoprotegerin , also known as osteoclastogenesis inhibitory factor , or tumor necrosis factor receptor superfamily member 11B , is a protein that in humans is encoded by the TNFRSF11B gene...
and RANK ligand
RANKL
Receptor activator of nuclear factor kappa-B ligand , also known as tumor necrosis factor ligand superfamily member 11 , TNF-related activation-induced cytokine , osteoprotegerin ligand , and osteoclast differentiation factor , is a protein that in humans is encoded by the TNFSF11 gene.RANKL is...
. Note that these molecules also regulate differentiation of the osteoclast.