SnoN Suppresses Maturation of Chondrocytes by Mediating Signal Cross-talk between Transforming Growth Factor-β and Bone Morphogenetic Protein Pathways

Abstract

Background: BMP signaling promotes chondrocyte maturation and, subsequently, endochondral ossification, whereas TGF-␤ signaling is inhibitory. Results: TGF-␤ induced SnoN to suppress BMP signaling and chondrocyte hypertrophy. Conclusion: SnoN mediates a signal cross-talk between TGF-␤ and BMP to regulate chondrocyte maturation. Significance: Our data revealed an effector of TGF-␤ signaling as a putative therapeutic molecular target for cartilage/bone regeneration or osteoarthritis.

The adipocyte clock controls brown adipogenesis via TGF-β/BMP signaling pathway

“…Most importantly, a mutually antagonistic relationship between TGF-b and BMP signal transduction has been wellcharacterized (Shi and Massagué, 2003), and loss of endogenous TGF-b signaling can augment BMP activity. Ski (Ehnert et al, 2012;Wang et al, 2000) and SnoN (Kawamura et al, 2012) are known BMP inhibitory molecules that can be induced by TGF-b to mediate the antagonism between these signaling events, whereas Smad6 is a ubiquitin ligase specific for BMP-activated Smad1/5/8 degradation. In Bmal1-deficient cells, as the attenuated TGF-b activity is accompanied by downregulation of SnoN, Ski and Smad6, a relief of these inhibitory mechanisms might have contributed to enhanced BMP signaling transduction.…”

“…However, the canonical BMP signaling targets Id1 and Id2 were markedly upregulated in Bmal1-deficient cells, additional evidence for augmented BMP activity in these cells as revealed by the findings of Smad5 phosphorylation and BMP reporter activity discussed above. Given that intracellular BMP signal transduction is subjected to negative-feedback regulation (Kavsak et al, 2000;Kawamura et al, 2012), we further analyzed whether loss of Bmal1 could affect negative regulatory mechanisms involved in the BMP signaling pathway to affect its activity. Interestingly, as demonstrated by expression analysis of BMP pathway inhibitory molecules (Fig.…”

Cartilage oligomeric matrix protein and its binding partners in the cartilage extracellular matrix: Interaction, regulation and role in chondrogenesis

“…This could be associated with the lowering of TGF-β1 signaling with advancing age in OA patients (van der Kraan et al, 2012). These studies paved the way for in-depth research on the interaction(s) of COMP with growth factors which are associated with cartilage/chondrocyte degeneration or maturation (Kawamura et al, 2012;Solorio et al, 2012).…”

Bone Morphogenic Protein (BMP) Signaling Up-regulates Neutral Sphingomyelinase 2 to Suppress Chondrocyte Maturation via the Akt Protein Signaling Pathway as a Negative Feedback Mechanism

“…Although the BMP-Smad pathway directly induces the inhibitory Smad, Smad6, to inhibit the phosphorylation of Smad1/5/8 as a negative feedback mechanism (27), and Smurf1 targets Smad6 and the BMP type I receptors to block BMP signaling (28,29), these inhibitory molecules are not specifically expressed in maturing chondrocytes. Recently, we reported that expression of the transcriptional repressor SnoN gradually increases in BMP-induced differentiating chondrocytes to suppress BMP signaling and the subsequent chondrocyte hypertrophic maturation (30). However, because SnoN partially blocked chondrocyte maturation, the mechanism regulating the rate of BMP signaling-driven chondrocyte differentiation in a cell-autonomous manner remains unclear.…”