TGF-beta signaling in chondrocyte terminal differentiation and osteoarthritis: modulation and integration of signaling pathways through receptor-Smads.
OBJECTIVE
Chondrocytes and alteration in chondrocyte differentiation play a central role in osteoarthritis. Chondrocyte differentiation is amongst others regulated by members of the transforming growth factor-beta (TGF-beta) superfamily. The major intracellular signaling routes of this family are via the receptor-Smads. This review is focused on the modulation of receptor-Smad signaling and how this modulation can affect chondrocyte differentiation and potentially osteoarthritis development.


METHODS
Peer reviewed publications published prior to April 2009 were searched in the Pubmed database. Articles that were relevant for the role of TGF-beta superfamily/Smad signaling in chondrocyte differentiation and for differential modulation of receptor-Smads were selected.


RESULTS
Chondrocyte terminal differentiation is stimulated by Smad1/5/8 activation and inhibited the by Smad2/3 pathway, most likely by modulation of Runx2 function. Several proteins and signaling pathways differentially affect Smad1/5/8 and Smad2/3 signaling. This will result in an altered Smad1/5/8 and Smad2/3 balance and subsequently have an effect on chondrocyte differentiation and osteoarthritis development.


CONCLUSIONS
Modulation of receptor-Smads signaling can be expect to play an essential role in both the regulation of chondrocyte differentiation and osteoarthritis development and progression.
van der Kraan
P M
PM
Experimental Rheumatology & Advanced Therapeutics, Radboud University, Nijmegen Medical Centre, Nijmegen, The Netherlands. p.vanderkraan@reuma.umcn.nl
Blaney Davidson
E N
EN
Blom
A
A
van den Berg
W B
WB
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation; D019902:Chondrocytes / Q000378:metabolism*; D006801:Humans; D051379:Mice; D010003:Osteoarthritis / Q000235:genetics / Q000378:metabolism*; D010012:Osteogenesis / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D051896:Smad Proteins, Receptor-Regulated / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D051155:Wnt1 Protein / Q000235:genetics
D051896:Smad Proteins, Receptor-Regulated; D016212:Transforming Growth Factor beta; D051155:Wnt1 Protein; D044767:Ubiquitin-Protein Ligases