Identification of the skeletal progenitor cells forming osteophytes in osteoarthritis

Anke J. Roelofs, Karolina Kania, Alexandra Rafipay, Meike Sambale, Stephanie T. Kuwahara, Fraser Collins, Joanna Smeeton, Maxwell A. Serowoky, Lynn Rowley, Hui Wang, René Gronewold, Chrysa Kapen, Simón Méndez-Ferrer, Christopher B. Little, John F. Bateman, Thomas Pap, Francesca V. Mariani, Joanna Sherwood, J. Gage Crump* (Corresponding Author), Cosimo de Bari* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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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 destabilization of the medial meniscus (DMM). Contributions of fluorescently labelled cells to osteophytes after 2 or 8 weeks, and their molecular identity, were analysed by histology, immunofluorescence staining, and in situ hybridisation. Pdgfrα-H2BGFP mice and Pdgfrα-CreER mice crossed with multi-colour 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.
Original languageEnglish
Pages (from-to)1625-1634
Number of pages10
JournalAnnals of the Rheumatic Diseases
Issue number12
Early online date22 Sept 2020
Publication statusPublished - Dec 2020

Bibliographical note

The authors thank all members of the Arthritis & Regenerative Medicine Laboratory at the University of Aberdeen; Shina Ardani and William Alton for their contributions to data acquisition; Animal Facility staff for care of our animals; staff in the Microscopy and Histology Facility and Iain Fraser
Cytometry Centre at the University of Aberdeen.
C.D.B., A.J.Ro, K.K., A.J.Ra., F.C. and H.W. were supported by funding from Versus Arthritis, formerly Arthritis Research UK (20775, 21156, 20050, 19429), and the Medical Research Council (MR/L020211/1). T.P., J.Sh., M.Sa., and R.G. were supported by funding from the Bundesministerium für Bildung und Forschung (BMBF) Overload-PrevOP consortium (01EC1408F) and the Innovative Medizinische Forschung (IMF) Program of the University Hospital Münster (Project I-SH121608). J.G.C., S.T.K. J.Sm., M.A.S., and F.V.M. were supported by funding from R01 AR069700. J.F.B, L.R. and C.B.L were supported by the National Health and Medical Research Council (NHMRC: APP1063133), and part funding was provided to J.F.B. by the Victorian Government‘s Operational Infrastructure Support Program to the Murdoch Children’s Research Institute. C.K. and S.M.F. were supported by funding from the Wellcome Trust (203151/Z/16/Z), Horizon2020 (ERC2014-CoG-648765), Cancer Research UK (C61367/A26670) and NHS Blood and Transplant


  • Osteoarthritis
  • osteophytes
  • stem cells
  • synovium
  • periosteum
  • fibroblasts
  • chondrocytes
  • arthritis
  • osteoarthritis
  • experimental


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