Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.6 (thromboplastin)
 13,278 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prothrombin is converted to thrombin by factor Xa in the cell-associated prothrombinase complex. Prothrombin is present in calcified bone matrix and thrombin exerts effects on osteoblasts as well as on bone resorption by osteoclasts. We investigated whether (1) osteoclasts display factor Xa-dependent prothrombinase activity and (2) osteoclasts express critical regulatory components upstream of the prothrombinase complex. The osteoclast differentiation factor RANKL induced formation of multinucleated TRAP positive cells concomitant with induction of prothrombinase activity in cultures of RAW 264.7 cells and bone marrow osteoclast progenitors. Expression analysis of extrinsic coagulation factors revealed that RANKL enhanced protein levels of factor Xa as well as of coagulation factor III (tissue factor). Inhibition assays indicated that factor Xa and tissue factor were involved in the control of prothrombinase activity in RANKL-differentiated osteoclasts, presumably at two stages (1) conversion of prothrombin to thrombin and (2) conversion of factor X to factor Xa, respectively. Activation of the extrinsic coagulation pathway during osteoclast differentiation through induction of tissue factor and factor Xa by a RANKL-dependent pathway indicates a novel role for osteoclasts in converting prothrombin to thrombin.
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PMID:RANKL induces components of the extrinsic coagulation pathway in osteoclasts. 2021 89

The serum protein prothrombin (PT) is proteolytically converted to thrombin during the coagulation cascade by the cell-associated prothrombinase complex. In vitro, RANKL-differentiated osteoclasts express tissue factor and coagulation factor Xa, which convert PT to thrombin (Karlstrom et al. Biochem Biophys Res Commun 394:593-599, 2010). The present study investigated the localization of PT in bone as well as the expression of PT mRNA in bone and osteoclasts. Herein, immunoblot analysis detected PT and smaller proteolytically cleaved fragments with sizes consistent with the action of prothrombinase in a protein fraction extracted with guanidine-HCl EDTA from mouse tibia. Light microscopic and ultrastructural immunohistochemistry demonstrated the presence of PT in the newly formed bone matrix of the metaphysis. Furthermore, fluorescent immunohistochemistry on metaphyseal trabecular bone showed that PT colocalized with MMP-9-expressing subepiphyseal osteoclasts, whereas cathepsin K-expressing osteoclasts were closely associated with PT of the bone matrix. RT-qPCR analysis revealed that PT mRNA was detected in tibia. Expression of PT mRNA in the tibia was 0.2% of the level in the liver. In addition, PT mRNA expression was increased by RANKL-induced differentiation of bone marrow macrophages to osteoclasts. The results demonstrate that PT is synthesized and proteolytically processed in bone. Furthermore, PT is present mainly in the newly formed bone matrix of the metaphyseal trabecular bone compartment in close association to osteoclasts. In addition, MMP-9-positive osteoclasts contain PT, and PT expression is increased during osteoclastogenesis.
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PMID:Localization and expression of prothrombin in rodent osteoclasts and long bones. 2119 74