Objectives To investigate the roles and regulatory mechanisms of synovial macrophages and their polarisation in the development of osteoarthritis (OA).
Methods Synovial tissues from normal patients and patients with OA were collected. M1 or M2-polarised macrophages in synovial tissues of patients with OA and OA mice were analysed by immunofluorescence and immunohistochemical staining. Mice with tuberous sclerosis complex 1 (TSC1) or Rheb deletion specifically in the myeloid lineage were generated and subjected to intra-articular injection of collagenase (collagenase-induced osteoarthritis, CIOA) and destabilisation of the medial meniscus (DMM) surgery to induce OA. Cartilage damage and osteophyte size were measured by Osteoarthritis Research Society International score and micro-CT, respectively. mRNA sequencing was performed in M1 and control macrophages. Mice and ATDC5 cells were treated with R-spondin-2 (Rspo2) or anti-Rspo2 to investigate the role of Rspo2 in OA.
Results M1 but not M2-polarised macrophages accumulated in human and mouse OA synovial tissue. TSC1 deletion in the myeloid lineage constitutively activated mechanistic target of rapamycin complex 1 (mTORC1), increased M1 polarisation in synovial macrophages and exacerbated experimental OA in both CIOA and DMM models, while Rheb deletion inhibited mTORC1, enhanced M2 polarisation and alleviated CIOA in mice. The results show that promoting the macrophage M1 polarisation leads to exacerbation of experimental OA partially through secretion of Rspo2 and activation of β-catenin signalling in chondrocytes.
Conclusions Synovial macrophage M1 polarisation exacerbates experimental CIOA partially through Rspo2. M1 macrophages and Rspo2 are potential therapeutic targets for OA treatment.
- knee osteoarthritis
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Handling editor Josef S Smolen
Contributors HZ and XB conceived the ideas for experimental designs, analysed data and wrote the manuscript. CL and CZ conducted the majority of the experiments and helped with manuscript preparation. ZW, JL and HW performed microcomputed tomography analyses and provided suggestions for the project. XL and YS performed immunohistochemistry and immunofluorescence and confocal imaging. SX and YZ conducted cell cultures and western blot experiments. CZ and DX collected human tissue samples. XB and DC developed the concept, supervised the project, conceived the experiments and critically reviewed the manuscript. HZ, CL and CZ contributed equally to this work.
Funding This work was supported by grants from the National Natural Science Foundation of China (Grant No 81625015, 81530070, 81772406 and 31529002) and the State Key Development Program for Basic Research of China (2015CB553602).
Competing interests None declared.
Patient consent Obtained.
Ethics approval Human study was approved by the Ethics Committee of the Third Affiliated Hospital of Southern Medical University. All animal experiments were approved by the Southern Medical University Committee Animal Care and Use Committee.
Provenance and peer review Not commissioned; externally peer reviewed.