RT Journal Article
SR Electronic
T1 Identification of the skeletal progenitor cells forming osteophytes in osteoarthritis
JF Annals of the Rheumatic Diseases
JO Ann Rheum Dis
FD BMJ Publishing Group Ltd and European League Against Rheumatism
SP 1625
OP 1634
DO 10.1136/annrheumdis-2020-218350
VO 79
IS 12
A1 Anke J Roelofs
A1 Karolina Kania
A1 Alexandra J Rafipay
A1 Meike Sambale
A1 Stephanie T Kuwahara
A1 Fraser L Collins
A1 Joanna Smeeton
A1 Maxwell A Serowoky
A1 Lynn Rowley
A1 Hui Wang
A1 René Gronewold
A1 Chrysa Kapeni
A1 Simón Méndez-Ferrer
A1 Christopher B Little
A1 John F Bateman
A1 Thomas Pap
A1 Francesca V Mariani
A1 Joanna Sherwood
A1 J Gage Crump
A1 Cosimo De Bari
YR 2020
UL http://ard.bmj.com/content/79/12/1625.abstract
AB Objectives Osteophytes are highly prevalent in osteoarthritis (OA) and are associated with pain and functional disability. These pathological outgrowths of cartilage and bone typically form at the junction of articular cartilage, periosteum and synovium. The aim of this study was to identify the cells forming osteophytes in OA.Methods Fluorescent genetic cell-labelling and tracing mouse models were induced with tamoxifen to switch on reporter expression, as appropriate, followed by surgery to induce destabilisation of the medial meniscus. Contributions of fluorescently labelled cells to osteophytes after 2 or 8 weeks, and their molecular identity, were analysed by histology, immunofluorescence staining and RNA in situ hybridisation. Pdgfrα-H2BGFP mice and Pdgfrα-CreER mice crossed with multicolour Confetti reporter mice were used for identification and clonal tracing of mesenchymal progenitors. Mice carrying Col2-CreER, Nes-CreER, LepR-Cre, Grem1-CreER, Gdf5-Cre, Sox9-CreER or Prg4-CreER were crossed with tdTomato reporter mice to lineage-trace chondrocytes and stem/progenitor cell subpopulations.Results Articular chondrocytes, or skeletal stem cells identified by Nes, LepR or Grem1 expression, did not give rise to osteophytes. Instead, osteophytes derived from Pdgfrα-expressing stem/progenitor cells in periosteum and synovium that are descendants from the Gdf5-expressing embryonic joint interzone. Further, we show that Sox9-expressing progenitors in periosteum supplied hybrid skeletal cells to the early osteophyte, while Prg4-expressing progenitors from synovial lining contributed to cartilage capping the osteophyte, but not to bone.Conclusion Our findings reveal distinct periosteal and synovial skeletal progenitors that cooperate to form osteophytes in OA. These cell populations could be targeted in disease modification for treatment of OA.