Differential expression of TGF-beta superfamily members and role of Smad1/5/9-signalling in chondral versus endochondral chondrocyte differentiation

作者：Dexheimer Verena; Gabler Jessica; Bomans Katharina; Sims Tanja; Omlor Georg; Richter Wiltrud^*

来源：Scientific Reports, 2016, 6(1): 36655.

DOI：10.1038/srep36655

Proteins of the transforming-growth-factor-beta (TGF-beta)-superfamily have a remarkable ability to induce cartilage and bone and the crosstalk of TGF-beta- and BMP-signalling pathways appears crucial during chondrocyte development. Aim was to assess the regulation of TGF-beta-superfamily members and of Smad2/3- and Smad1/5/9-signalling during endochondral in vitro chondrogenesis of mesenchymal stromal cells (MSC) relative to chondral redifferentiation of articular chondrocytes (AC) to adjust chondrocyte development of MSC towards a less hypertrophic phenotype. While MSC increased BMP4 and BMP7 and reduced TGFBR2 and TGFBR3-expression during chondrogenesis, an opposite regulation was observed during AC-redifferentiation. Antagonists CHRD and CHL2 rose significantly only in AC-cultures. AC showed higher initial BMP4, pSmad1/5/9 and SOX9 protein levels, a faster (re-) differentiation but a similar decline of pSmad2/3-and pSmad1/5/9-signalling versus MSC-cultures. BMP-4/7-stimulation of MSC-pellets enhanced SOX9 and accelerated ALP-induction but did not shift differentiation towards osteogenesis. Inhibition of BMP-signalling by dorsomorphin significantly reduced SOX9, raised RUNX2, maintained collagen-type-II and collagen-type-X lower and kept ALP-activity at levels reached at initiation of treatment. Conclusively, ALK1,2,3,6-signalling was essential for MSC-chondrogenesis and its prochondrogenic rather than prohypertrophic role may explain why inhibition of canonical BMP-signalling could not uncouple cartilage matrix production from hypertrophy as this was achieved with pulsed PTHrP-application.

• 出版日期2016-11-16