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001-es BibID:	BIBFORM049124
035-os BibID:	PMID:24333667
Első szerző:	Juhász Tamás (biológus, orvosbiológus)
Cím:	Mechanical loading stimulates chondrogenesis via the PKA/CREB-Sox9 and PP2A pathways in chicken micromass cultures / Tamás Juhász, Csaba Matta, Csilla Somogyi, Éva Katona, Roland Takács, Rudolf Ferenc Soha, István A. Szabó, Csaba Cserháti, Róbert Sződy, Zoltán Karácsonyi, Éva Bakó, Pál Gergely, Róza Zákány
Dátum:	2014
ISSN:	0898-6568
Megjegyzések:	Biomechanical stimuli play important roles in the formation of articular cartilage during early foetal life, and optimal mechanical load is a crucial regulatory factor of adult chondrocyte metabolism and function. In this study, we undertook to analyse mechanotransduction pathways during in vitro chondrogenesis. Chondroprogenitor cells isolated from limb buds of 4-day-old chicken embryos were cultivated as high density cell cultures for 6days. Mechanical stimulation was carried out by a self-designed bioreactor that exerted uniaxial intermittent cyclic load transmitted by the culture medium as hydrostatic pressure and fluid shear to differentiating cells. The loading scheme (0.05Hz, 600Pa; for 30min) was applied on culturing days 2 and 3, when final commitment and differentiation of chondroprogenitor cells occurred in this model. The applied mechanical load significantly augmented cartilage matrix production and elevated mRNA expression of several cartilage matrix constituents, including collagen type II and aggrecan core protein, as well as matrix-producing hyaluronan synthases through enhanced expression, phosphorylation and nuclear signals of the main chondrogenic transcription factor Sox9. Along with increased cAMP levels, a significantly enhanced protein kinase A (PKA) activity was also detected and CREB, the archetypal downstream transcription factor of PKA signalling, exhibited elevated phosphorylation levels and stronger nuclear signals in response to mechanical stimuli. All the above effects were diminished by the PKA-inhibitor H89. Inhibition of the PKA-independent cAMP-mediators Epac1 and Epac2 with HJC0197 resulted in enhanced cartilage formation, which was additive to that of the mechanical stimulation, implying that the chondrogenesis-promoting effect of mechanical load was independent of Epac. At the same time, PP2A activity was reduced following mechanical load and treatments with the PP2A-inhibitor okadaic acid were able to mimic the effects of the intervention. Our results indicate that proper mechanical stimuli augment in vitro cartilage formation via promoting both differentiation and matrix production of chondrogenic cells, and the opposing regulation of the PKA/CREB-Sox9 and the PP2A signalling pathways is crucial in this phenomenon.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban folyóiratcikk Doktori iskola Mechanotransduction Chondrocyte differentiation Extracellular matrix H89 Okadaic acid Epac
Megjelenés:	Cellular Signalling. - 26 : 3 (2014), p. 468-482. -
További szerzők:	Matta Csaba (1980-) (molekuláris biológus, genetikus, angol szakfordító) Somogyi Csilla (1983-) (biológus, angol-magyar szakfordító) Katona Éva (1986-) (molekuláris biológus) Takács Roland Ádám (1985-) (molekuláris biológus, biokémikus) Soha Rudolf Ferenc (1986-) (fizikus) Szabó István András (1956-) (fizikus) Cserháti Csaba (1963-) (fizikus) Sződy Róbert Karácsonyi Zoltán (1975-) (ortopéd és baleseti sebész) Bakó Éva (1958-) (biokémikus) Gergely Pál (1947-) (biokémikus) Zákány Róza (1963-) (anatómus-, kötőszövetbiológus)
Pályázati támogatás:	TÁMOP-4.2.2.A-11/1/KONV-2012-0025 TÁMOP TÁMOP-4.2.2/B-10/1-2010-0024 TÁMOP Molekuláris Orvostudomány Doktori Iskola TÁMOP-4.2.2.A-11/1/KONV-2012-0036 TÁMOP TÁMOP-4.2.4.A/2-11-1-2012-0001 TÁMOP CNK80709 OTKA
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