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Amelioration of post-traumatic osteoarthritis via nanoparticle depots delivering small interfering RNA to damaged cartilage

Abstract

The progression of osteoarthritis is associated with inflammation triggered by the enzymatic degradation of extracellular matrix in injured cartilage. Here we show that a locally injected depot of nanoparticles functionalized with an antibody targeting type II collagen and carrying small interfering RNA targeting the matrix metalloproteinase 13 gene (Mmp13), which breaks down type II collagen, substantially reduced the expression of MMP13 and protected cartilage integrity and overall joint structure in acute and severe mouse models of post-traumatic osteoarthritis. MMP13 inhibition suppressed clusters of genes associated with tissue restructuring, angiogenesis, innate immune responses and proteolysis. We also show that intra-articular injections of the nanoparticles led to greater reductions in disease progression than either a single injection or weekly injections of the steroid methylprednisolone. Sustained drug retention by targeting collagen in the damaged extracellular matrix of osteoarthritic cartilage may also be an effective strategy for the treatment of osteoarthritis with other disease-modifying drugs.

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Fig. 1: Synthesis of mAbCII-siNPs.
Fig. 2: Characterization of in vitro chemico-physical, gene silencing and cartilage retention of mAbCII-siNPs relative to bare and mAbCtrl-functionalized siNPs.
Fig. 3: mAbCII-siNP/siMMP13 is retained locally and potently silences Mmp13 expression relative to bare and mAbCtrl-functionalized siNPs in the knee joints of a short-term mouse model of PTOA.
Fig. 4: Long-term Mmp13 silencing reduces MMP13 protein levels in cartilage and synovium and protects mechanically loaded joints from OA progression.
Fig. 5: mAbCII-siNP/siMMP13 treatment provides whole-knee-joint protection by reducing synovial thickening, osteophyte formation and meniscal mineralization.
Fig. 6: Mmp13 silencing by mAbCII-siNP/siMMP13 treatment globally impacts gene-expression patterns in mechanically loaded PTOA joints.
Fig. 7: Clinical gold standard steroid treatment with methylprednisolone does not provide DMOAD effects in a long-term PTOA mouse model, unlike mAbCII-siNP/siMMP13 treatment.

Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. Raw and normalized nanoString datasets are available at the Gene Expression Omnibus under accession identifier GSE171031. The remaining raw and analysed datasets from the study are too large to be publicly shared, but they are available for research purposes from the corresponding author on reasonable request.

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Acknowledgements

The authors acknowledge the assistance of the Vanderbilt TPSR. The TPSR is supported by National Cancer Institute/National Insitutes for Health (NIH) Cancer Center Support Grant 2P30 CA068485-14. Dynamic light scattering was conducted at the Vanderbilt Institute of Nanoscale Sciences and Engineering. Bone analysis by microCT was supported in part by the NIH (S10RR027631-01). We thank C. B. Wiese, J. R. Johnson and R. Mernaugh for technical assistance. The VANTAGE core performed nanoString QC and hybridization, and is supported by the Vanderbilt Ingram Cancer Center (P30 CA68485), the Vanderbilt Vision Center (P30 EY08126) and NIH/National Centre for Research Resources (G20 RR030956). We thank the Department of Defense (DOD CDMRP OR130302), NIH (NIH R01 CA224241 and NIH R01 EB019409), NIH (NIGMS T32GM007347), the Veterans Association Merit Award BX004151, the National Science Foundation Graduate Research Fellowship Program (NSF GRF 2016212929), the Natural Sciences and Engineering Research Council of Canada (NSERC) and the Rheumatology Research Foundation (RRF) for support.

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S.K.B., C.L.D., K.A.H., L.J.C. and J.M.C. designed the project and experiments. S.K.B. synthesized the polymers and conjugates and formulated nanoparticles for all experiments. S.K.B. and F.Y. conducted all animal experiments. S.K.B., M.A.J. and D.D.L. performed nanoparticle characterization. S.K.B., F.Y., J.M.C. and D.D.L. imaged and collected tissues. L.E.H. and H.C. conducted histology and immunohistochemistry, with L.E.H. performing blinded scoring of histology. S.K.B., C.L.D. and J.M.C. wrote the manuscript. All authors reviewed and commented on the manuscript.

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Correspondence to Craig L. Duvall.

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Bedingfield, S.K., Colazo, J.M., Yu, F. et al. Amelioration of post-traumatic osteoarthritis via nanoparticle depots delivering small interfering RNA to damaged cartilage. Nat Biomed Eng 5, 1069–1083 (2021). https://doi.org/10.1038/s41551-021-00780-3

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