FIGURE 10.

Working model for regulation of TGFβ1 signaling in fibroblasts by hyaluronan-bound aggrecan, ADAMTS5, and CD44. In the ts5^−/− genotype (left), aggrecan is retained on CD44-bound HA and continues to accumulate due to the absence of TS5. This promotes binding of TGFβ1 to TGFβRII/ALK-1 leading to Smad1/5/8 phosphorylation, which promotes further commitment of target cells to an epithelioid/aggregating phenotype. Conversely, in WT and Cd44^−/− cells (right), removal of aggrecan-HA complexes favors association of TGFβ1-TGFβRII with ALK5 resulting in robust Smad2/3 phosphorylation and expression of a fibroblastic/contractile phenotype.