Intrinsic regeneration of osteoarthritic cartilage by unloading involves peri-articular stem cell activity: a joint effort

Concept

Spontaneous cartilage repair has recently been recognized as proof of concept in man. This team will delineate the unknown mechanisms by which mesenchymal stem cells (MSCs) in the context of the intraarticular milieu are involved in this repair activity.

Facts and figures

Project lead
F Lafeber
UMC Utrecht
S.Mastbergen@UMCUtrecht.nl
FOREUM research grant: € 300.000
2016 - 2019

Meet the team

F Lafeber
UMC Utrecht
S Mastbergen
UMC Utrecht
D McGonagle
University of Leeds
F Berenbaum
Université Pierre et Marie Curie

Interim results

Upon distraction it suggested that MSC number initially decline in the synovial fluid (SF) (figure 1A-B). MSCs present in the SF showed changes in their gene expression profile upon KJD, most clearly observed during the treatment (3 weeks; figure 1C).

GDF5 and Grem1 presented with a statistically significant increased expression (p<0.05) during treatment while FAB4 expression was decreased. ACAN, PTH1R, and DDR expression had the tendency to increase over time. ADAMTS4, SOX9 and PTHLH expression showed a trend to decrease over time.

Preliminary proteomics analysis on the SF samples of the first 5 patients indicate a clear difference can be seen in the samples before vs during and after distraction (see figure 2). Exact interpretation needs further analyses of the remaining patients. In parallel to this study we have analyzed (in collaboration with Oxford) the synovial fluid of joint distraction patients (additional group in addition to this project) for mechano-sensitive de/regenerative markers. Of the 10 markers studied 4 were significant elevated (IL-6, TGF-B, MCP-1, FGF-2), 2 significant downregulated (Activin-A, LTBP-2) and 4 were not changed (IL-8, MMP-3, TIMP-1, TSG-6). These results can give further guidance to the analyses performed in Paris.

This explorative study provides for the first-time data on changes in SF MSC number and their gene and protein expression profiles upon knee joint distraction. As such, first clues are provided for the involvement of MSCs in the regenerative process induced by joint distraction for end-stage knee OA. Final results are expected this summer. Further studies are necessary to unravel the processes involved

Publications 2019-2020

Understanding joint preservation, new insights from knee joint distraction
Simon Mastbergen, Invited speaker at EORS 2019, Maastricht October 2019; Invited speaker at 6th Joint Preservation Congress at Warsaw, Poland September 2019

The catabolic-to-anabolic shift in the osteoarthritic cartilage after knee joint distraction in dogs occurs after the distraction period. M.Teunissen, J. Popov-Celeketic, K.Coeleveld, B.P.Meij, F.P.J.G.Lafeber, M.A.Tryfonidou, S.C.Mastbergen

Oral presentation at EORS 2019, Maastricht October 2019

Analysis of mechano-sensitive pathway markers in the synovial fluid during joint distraction.

Fiona E Watt, Benjamin Hamid, Cesar Garriga, Andrew Judge, Renata Hrusecka, Roel Custers, Floris Lafeber, Simon Mastbergenⱡ, Tonia Vincentⱡ ⱡjoint last author
Poster presentation at ORS February 2019

Osteoarthritis Cartilage. 2020 Mar;28(3):324-333

Abstracts EULAR 2019

FRI0518: Longitudinal evaluation of synovial fluid and synovial fluid MSC transcript changes in subjects undergoing joint distraction

Presentation at EULAR 2020

Joint distraction in OA; an update and molecular insights
S.C. Mastbergen

Invited speaker presentation
Session Cartilage - heal thyself! Friday, 05 June, 2020
(08:15 AM - 09:45 AM).