Regulation of the phenotypic stability of chondrocytes by transmembrane heparan sulfate proteoglycans of the syndecan family
Final Report Abstract
Transmembrane heparan sulfate proteoglycans of the syndecan (Sdc) family have been proposed to bind a large variety of proteins and thereby mediate an array of different functions in cells. Sdc-4 is of major importance during stress situations like fracture healing, wound healing and in osteoarthritis (OA). The main topic of this fellowship was to investigate the influence of Sdc2 and Sdc4 dependent signalling on the phenotypic stability of chondrocytes. We observed very early during this project that Sdc2 was barely expressed during OA. Therefore, we focussed mainly on the influence of Sdc4. We found that Sdc4 is critically involved in age related stiffening of the extracellular matrix in cartilage. The stiffening of cartilage regulates the sensitivity of chondrocytes towards canonical Wnt signalling thereby making them more prone to undergo Wnt induced hypertrophic differentiation (these data are currently being prepared for publication). It has been proposed before that inhibition of matrix crosslinking by inhibition of Lox is a therapeutic option for OA prevention. The data of this project explain the biochemical reasons for the protective effect of LOX inhibition and might give rise to new targets in the prevention of age related OA. There are LOX inhibitors on the market that are currently used as treatment for fibrosis. We plan to use these inhibitors in animal models of OA to prevent age related OA and maybe as a therapeutic option for early OA. This will be the topic of a follow up project after publication of the data from this project. We have also shown that inhibition of canonical WNT signalling using specific inhibitors attenuated the dedifferentiation of early OA cartilage, whereas late OA cartilage could not be rescued. These data indicate that there might be a treatment window for Wnt inhibitors in early OA. Another aspect of this fellowship was the investigation of Sdc4 shedding and its role during OA. We found that the amount of shed Sdc4 in synovial fluid directly correlated with OA severity, making shed Sdc4 a good biomarker for OA. We plan to validate the use of shed Sdc4 as a biomarker testing the potential use as marker for cartilage turn-over and cartilage regeneration in a bigger cohort. There is currently no biomarker available to measure the regenerative capacity of cartilage during therapeutic treatment, making the use of novel therapeutic strategies for cartilage regeneration difficult to measure. Shed Sdc4 might be a marker to visualize the cartilage turnover and regeneration. This will be tested in a follow up project.
Publications
- (2021) MMP-9 mediated Syndecan-4 shedding correlates with osteoarthritis severity. Osteoarthritis and cartilage 29 (2) 280–289
Bollmann, M.; Pinno, K.; Ehnold, L. I.; Märtens, N.; Märtson, A.; Pap, T.; Stärke, C.; Lohmann, C. H.; Bertrand, J.
(See online at https://doi.org/10.1016/j.joca.2020.10.009) - Soluble syndecans: Biomarkers for diseases and therapeutic options. Br J Pharmacol. 2018 Jun 21
Bertrand J, Bollmann M
(See online at https://doi.org/10.1111/bph.14397) - Targeting β-catenin dependent Wnt signaling via peptidomimetic inhibitors in murine chondrocytes and OA cartilage. Osteoarthritis Cartilage. 2018 Mar 17
Held A, Glas A, Dietrich L, Bollmann M, Brandstädter K, Grossmann TN, Lohmann CH, Pap T, Bertrand J
(See online at https://doi.org/10.1016/j.joca.2018.02.908) - Antibody-mediated inhibition of syndecan-4 dimerisation reduces interleukin (IL)-1 receptor trafficking and signalling. Ann Rheum Dis. 2020 Feb 24
Godmann L; Bollmann M; Korb-Pap A; König U; Sherwood J; Beckmann D; Mühlenberg K; Echtermeyer F; Whiteford J; De Rossi G; Pap T; Bertrand J
(See online at https://doi.org/10.1136/annrheumdis-2019-216847) - BCP crystals promote chondrocyte hypertrophic differentiation in OA cartilage by sequestering Wnt3a. Ann Rheum Dis. 2020 May 5
Bertrand J, Kräft T, Gronau T, Sherwood J, Rutsch F, Lioté F, Dell’Accio F, Lohmann CH, Bollmann M, Held A, Pap T
(See online at https://doi.org/10.1136/annrheumdis-2019-216648)
