osteoclast

破骨細胞 　

WordNet

1. cell that functions in the breakdown and resorption of bone tissue

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/12/20 16:03:01」(JST)

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Osteoclast
Light micrograph of an osteoclast displaying typical distinguishing characteristics: a large cell with multiple nuclei and a "foamy" cytosol.
Details
Latin	osteoclastus
Identifiers
Code	TH H2.00.03.7.00005
Anatomical terminology

An osteoclast (from the Greek words for "bone" (ὀστέον), and "broken" (κλαστός)) is a type of bone cell that breaks down bone tissue. This function is critical in the maintenance, repair, and remodelling of bones of the vertebral skeleton. 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. This process also helps regulate the level of blood calcium.

Morphology

Tartrate resistant acid phosphatase positive osteoclast in cell culture

Illustrated cross-section of an activated osteoclast

Osteoclasts were discovered by Kolliker in 1873. An osteoclast is a large multinucleated cell and human osteoclasts on bone typically have five nuclei and are about 150-200 µm in diameter. Giant osteoclasts can occur in some diseases, including Paget's disease of bone and bisphosphonate toxicity. When osteoclast-inducing cytokines are used to convert macrophages 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 due to the not-natural substrate. 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, 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 phosphatase. This permits characterization of osteoclasts by their staining for high expression of tartrate resistant acid phosphatase (TRAP) 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.

Osteoclast Physiology

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. 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.

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

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 osteoblasts 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 (receptor activator of nuclear factor κβ ligand) 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. It may be important to note that while osteoclasts are derived from the hematopoietic lineage, osteoblasts are derived from mesenchymal stem cells.

Function

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 (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 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 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 is the major protease involved in the degradation of type I collagen and other noncollagenous proteins. Mutations in the cathepsin K gene are associated with pycnodysostosis, a hereditary osteopetrotic 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 functional secretory domain. Within these intercellular vesicles, cathepsin K, along with reactive oxygen species generated by TRAP, further degrades the bone extracellular matrix.

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.

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 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.

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). 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.

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
• Osteoclasts at the US National Library of Medicine Medical Subject Headings (MeSH)
• The Life of Osteoclast
• Animation by Random42 Medical Animation on the role of osteoclasts in bone remodeling

UpToDate Contents

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• 1. 骨格の正常な発達および骨形成ならびに骨吸収の調節 normal skeletal development and regulation of bone formation and resorption
• 2. 乳癌からの骨転移マネージメントにおける破骨細胞阻害 osteoclast inhibition in the management of bone metastases from breast cancer
• 3. 進行性前立腺癌における骨転移のマネージメント management of bone metastases in advanced prostate cancer
• 4. 骨粗鬆症の病因 pathogenesis of osteoporosis
• 5. 骨代謝の生理学および生化学的マーカー bone physiology and biochemical markers of bone turnover

English Journal

• Hyperbaric oxygen therapy modulates serum OPG/RANKL in femoral head necrosis patients.

• Vezzani G1, Quartesan S1, Cancellara P1, Camporesi E2, Mangar D2, Bernasek T3, Dalvi P2, Yang Z4, Paoli A1, Rizzato A1, Bosco G1.
• Journal of enzyme inhibition and medicinal chemistry.J Enzyme Inhib Med Chem.2017 Dec;32(1):707-711. doi: 10.1080/14756366.2017.1302440.
• PMID 28385082

• The molecular pathophysiology of chronic non-bacterial osteomyelitis (CNO)-a systematic review.

• Hofmann SR1, Kapplusch F1, Mäbert K1, Hedrich CM2,3,4.
• Molecular and cellular pediatrics.Mol Cell Pediatr.2017 Dec;4(1):7. doi: 10.1186/s40348-017-0073-y. Epub 2017 Jul 6.
• PMID 28685269

• Atorvastatin-loaded micelles with bone-targeted ligand for the treatment of osteoporosis.

• Xie Y1, Tan X2, Huang J1, Huang H1, Zou P3, Hu J4.
• Drug delivery.Drug Deliv.2017 Nov;24(1):1067-1076. doi: 10.1080/10717544.2017.1347966.
• PMID 28705021

Japanese Journal

• 抗RANKL抗体 (特集 骨粗鬆症の薬物療法 : 最新の薬物治療を中心に)

• 日本臨床 73(10), 1690-1695, 2015-10
• NAID 40020597832

• 好気的代謝と共役するエピジェネティック制御を介した新たな破骨細胞制御機構

• 臨床免疫・アレルギー科 = Clinical immunology & allergology 64(3), 285-288, 2015-09
• NAID 40020592843

• 多光子励起顕微鏡を用いた骨組織細胞動態イメージング

• 臨床免疫・アレルギー科 = Clinical immunology & allergology 64(2), 194-199, 2015-08
• NAID 40020563405

Related Links

• Osteoclast | definition of osteoclast by Medical dictionary

osteoclast [os´te-o-klast″] 1. a large, multinuclear cell frequently associated with resorption of bone. 2. a surgical instrument used for osteoclasis. adj., adj osteoclas´tic. os·te·o·clast (os'tē-ō-klast'), 1. A large multinucleated cell ...

• Osteoclast differentiation and activation.

1. Nature. 2003 May 15;423(6937):337-42. Osteoclast differentiation and activation. Boyle WJ(1), Simonet WS, Lacey DL. Author information: (1)Protein Pathways, Inc., Woodland Hills, California 91367, USA. bboyle@ ...

Related Pictures

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★リンクテーブル★

リンク元	「破骨細胞」「osteoclastic」「odontoclast」
拡張検索	「osteoclast formation」「osteoclast activating factor」

「破骨細胞」

　　[★]

英

osteoclast OC

ラ

osteoclastus

関

骨芽細胞

• 骨の吸収を行う多核の巨細胞。

「osteoclastic」

　　[★]

• adj.

• 破骨細胞の、骨破壊性の

関

osteoclast

「odontoclast」

　　[★]

破歯細胞

関

osteoclast

「osteoclast formation」

　　[★]

• 破骨細胞形成

関

osteoclastogenesis

「osteoclast activating factor」

　　[★] 破骨細胞活性化因子