Glycosaminoglycans are known to bind biological mediators thereby modulating
their biological activity. Sulfated hyaluronans (sHA) were reported to
strongly interact with transforming growth factor (TGF)-β1 leading to impaired
bioactivity in fibroblasts. The underlying mechanism is not fully elucidated
yet. Examining the interaction of all components of the TGF-β1:receptor
complex with sHA by surface plasmon resonance, we could show that highly
sulfated HA (sHA3) blocks binding of TGF-β1 to its TGF-β receptor-I (TβR-I)
and -II (TβR-II). However, sequential addition of sHA3 to the TβR-II/TGF-β1
complex led to a significantly stronger recruitment of TβR-I compared to a
complex lacking sHA3, indicating that the order of binding events is very
important. Molecular modeling suggested a possible molecular mechanism in
which sHA3 could potentially favor the association of TβR-I when added
sequentially. For the first time bioactivity of TGF-β1 in conjunction with sHA
was investigated at the receptor level. TβR-I and, furthermore, Smad2
phosphorylation were decreased in the presence of sHA3 indicating the
formation of an inactive signaling complex. The results contribute to an
improved understanding of the interference of sHA3 with TGF-β1:receptor
complex formation and will help to further improve the design of functional
biomaterials that interfere with TGF-β1-driven skin fibrosis