Abstract
BackgroundThe purpose of this study was to investigate the therapeutic efficacy of intravenously administered immunoselected STRO-3 + mesenchymal precursor cells (MPCs) on clinical scores, joint pathology and cytokine production in an ovine model of monoarthritis.MethodsMonoarthritis was established in 16 adult merino sheep by administration of bovine type II collagen into the left hock joint following initial sensitization to this antigen. After 24 h, sheep were administered either 150 million allogeneic ovine MPCs (n = 8) or saline (n = 8) intravenously (IV). Lameness, joint swelling and pain were monitored and blood samples for leukocytes and cytokine levels were collected at intervals following arthritis induction. Animals were necropsied 14 days after arthritis induction and gross and histopathological evaluations were undertaken on tissues from the arthritic (left) and contralateral (right) joints.ResultsMPC-treated sheep demonstrated significantly reduced clinical signs of lameness, joint pain and swelling compared with saline controls. They also showed decreased cartilage erosions, synovial stromal cell activation and angiogenesis. This was accompanied by decreased infiltration of the synovial tissues by CD4+ lymphocytes and CD14+ monocytes/macrophages. Over the 3 days following joint arthropathy induction, the numbers of neutrophils circulating in the blood and plasma concentrations of activin A were significantly reduced in animals administered MPCs.ConclusionsThe results of this study have demonstrated the capacity of IV-administered MPCs to mitigate the clinical signs and some of the inflammatory mediators responsible for joint tissue destruction in a large animal model of monoarthritis.
Highlights
The purpose of this study was to investigate the therapeutic efficacy of intravenously administered immunoselected STRO-3 + mesenchymal precursor cells (MPCs) on clinical scores, joint pathology and cytokine production in an ovine model of monoarthritis
Macroscopic scoring of articular cartilage from hock joints The cartilage on the surface of the talus was assessed using a 5-point scale based on the Osteoarthritis Research Society International (OARSI) recommendations for macroscopic scoring of cartilage pathology [31], but simplified because the primary cartilage injuries were confined to the central trochlear groove of the talus, rather than the whole joint surface as we have described previously [14]
SF samples were collected only at the time of necropsy, sampling at earlier time points in the study may have revealed differences in the synovial fluid cellular composition associated with MPC treatment; this procedure was excluded from the study protocol due to the risk of inducing inflammatory changes within the joint from repeated joint sampling
Summary
The purpose of this study was to investigate the therapeutic efficacy of intravenously administered immunoselected STRO-3 + mesenchymal precursor cells (MPCs) on clinical scores, joint pathology and cytokine production in an ovine model of monoarthritis. Neutrophils play an important role in the initiation and progression of rheumatoid arthritis (RA) where they accumulate in large numbers within the synovium and synovial fluid (SF) of the joint affected joints [1,2,3,4,5]. Apart from their potent cytotoxic properties they contribute to cytokine and chemokine release/activation. The ovine CIA model has advantages over rodent models, with respect to the ease of access to target joints for intra-articular injections, collection of multiple fluid samples and the ability to cannulate the lymphatic ducts in order to monitor the cell populations exiting the joint [16]
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