Mechanical motion promotes expression of Prg4 in articular cartilage via multiple CREB-dependent, fluid flow shear stress-induced signaling pathways.
Lubricin is a secreted proteoglycan encoded by the Prg4 locus that is abundantly expressed by superficial zone articular chondrocytes and has been noted to both be sensitive to mechanical loading and protect against the development of osteoarthritis. In this study, we document that running induces maximal expression of Prg4 in the superficial zone of knee joint articular cartilage in a COX-2-dependent fashion, which correlates with augmented levels of phospho-S133 CREB and increased nuclear localization of CREB-regulated transcriptional coactivators (CRTCs) in this tissue. Furthermore, we found that fluid flow shear stress (FFSS) increases secretion of extracellular PGE2, PTHrP, and ATP (by epiphyseal chondrocytes), which together engage both PKA- and Ca(++)-regulated signaling pathways that work in combination to promote CREB-dependent induction of Prg4, specifically in superficial zone articular chondrocytes. Because running and FFSS both boost Prg4 expression in a COX-2-dependent fashion, our results suggest that mechanical motion may induce Prg4 expression in the superficial zone of articular cartilage by engaging the same signaling pathways activated in vitro by FFSS that promote CREB-dependent gene expression in this tissue.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA;
Hiroyasu
H
Ogawa
Elena
E
Kozhemyakina
Han-Hwa
HH
Hung
Alan J
AJ
Grodzinsky
Andrew B
AB
Lassar
D000255:Adenosine Triphosphate / Q000378:metabolism; D000483:Alleles; D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002358:Cartilage, Articular / Q000378:metabolism*; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000235:genetics; D011509:Proteoglycans / Q000235:genetics* / Q000378:metabolism*; D011995:Recombination, Genetic / Q000235:genetics; D015398:Signal Transduction; D013312:Stress, Physiological / Q000235:genetics; D000099158:Proteoglycan 4
D000255:Adenosine Triphosphate; D050882:CREB-Binding Protein; D002118:Calcium; D011509:Proteoglycans; C498837:Prg4 protein, mouse; D000099158:Proteoglycan 4; C494364:Crebbp protein, mouse
CREB; PGE2; PTHrP; Prg4/lubricin; articular cartilage; extracellular ATP