A study in Annals of the Rheumatic Diseases has identified an important function of connective tissue growth factor (CTGF) in response to mechanical stress and cartilage damage typically associated with osteoarthritis. “We have uncovered what we think may be the principal mechanism of action of CTGF and demonstrate a new mechanism by which TGFβ is activated in response to tissue injury,” says corresponding author Tonia Vincent.

Credit: Susanne Harris/ Springer Nature Limited

The pericellular matrix (PCM) surrounds and isolates chondrocytes from the stiffer extracellular matrix (ECM), and is thereby thought to be highly responsive to mechanical force. “We have previously shown that an important mechanism by which cartilage responds to sterile mechanical injury is by liberating growth factors bound to heparan sulphate in the PCM,” notes Vincent. Her group has worked extensively on one of the best characterized of these responses, the release and activation of fibroblast-like growth factor 2.

In the new study, the researchers detect CTGF in the PCM of human articular cartilage and its release into culture medium upon incision damage to explants. They also present microarray evidence that stimulation of chondrocytes with recombinant CTGF induces genes involved in canonical TGFβ signalling.

Importantly, gel comigration and co-immunoprecipitation data show that CTGF interacts covalently with TGFβ, functioning as a binding protein to sequester latent TGFβ in the PCM until its release on injury. Subsequent activation of this complex, the researchers believe, results from the complex binding to TGFβ receptor 3 on the chondrocyte.

CTGF interacts covalently with TGFβ

The proposed function of CTGF is also supported by in vivo data. Vincent’s team found that less TGFβ was released in response to hip avulsion (to model cartilage injury) of mice with tamoxifen-induced knockout of floxed Ctgf, compared with floxed mice not treated with tamoxifen as a control.

However, unexpectedly, the Ctgf-deleted mice were more resistant to destabilization of the medial meniscus (osteoarthritis model), an effect attributable to increased thickness of the cartilage associated with constitutively active SMAD2.

To explain this surprising phenotype further data are needed; Vincent speculates that this effect may be due to over-compensation by other TGFβ family members.