SMAD2 and Loeys-Dietz syndrome: Interestingly, a similar paradox is documented in patients with Loeys-Dietz syndrome where loss of function of TGFβ (through mutations in TGFβ receptors or ligands) is associated with unexplained high SMAD2 phosphorylation in patient tissues.49 Another possible explanation for the increased SMAD2 phosphorylation in the chondrocytes of CTGFcKO mice is that there is increased soluble latent TGFβ either because it is not being sequestered in the matrix of cartilage or because it is derived from other cells of the joint.