Protein kinases in chondrocyte signaling and osteoarthritis.
Protein kinases, particularly mitogen-activated protein kinases and receptor-tyrosine kinases play crucial roles in mammalian cellular metabolism by regulating intracellular signaling pathways that control proliferation, differentiation, cytokine gene induction and cytokine responsiveness, matrix metalloproteinase gene expression, mechanical transduction, as well as programmed cell death (apoptosis). Many of these pathways are also important components of cartilage homeostasis because alterations in intracellular signaling pathways appear to play a prominent role in chondrocyte dysfunction that is part of osteoarthritis pathogenesis and disease progression. Several mitogen-activated protein kinases and receptor-tyrosine kinases have been characterized as participating in chondrocyte signaling pathways. They are c-Jun-amino-terminal protein kinase, p38 kinase, extracellular signal-regulated protein kinase, and Ror2. Janus kinases and signal transducers and activators of transcription factors (Janus kinase/signal transducers and activators of transcription pathway) are also implicated in modulating the chondrogenic phenotype. Mitogen-activated protein kinase activation is required for their role as phosphorylating enzymes. Activation results from mitogen-activated protein kinase phosphorylation carried out by at least seven upstream kinases known as mitogen-activated protein kinase kinases. Additional upstream kinases (for example, MKKKKs and MKKKs) often require low molecular weight GTP-binding proteins to mediate the mitogen-activated protein-kinase kinases cascade. Identifying the functions of mitogen-activated protein kinases in normal and aging cartilage and the extent to which mitogen-activated protein kinases may be altered in osteoarthritis cartilage and synovium will be critical for developing novel therapies for osteoarthritis management.
Malemud
Charles J
CJ
Department of Medicine, Case Western Reserve University School of Medicine, University Hospitals of Cleveland, Cleveland, OH 44106, USA. cjm4@cwru.edu
D000818:Animals; D017209:Apoptosis; D019902:Chondrocytes / Q000201:enzymology*; D020219:Chondrogenesis / Q000235:genetics; D016207:Cytokines / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D010003:Osteoarthritis / Q000201:enzymology* / Q000473:pathology; D010641:Phenotype; D011494:Protein Kinases / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology
D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D011494:Protein Kinases; D020794:Receptor Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases