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Series GSE171031 Query DataSets for GSE171031
Status Public on Apr 17, 2021
Title Matrix-anchored Nanoparticles for MMP13 RNA Interference Block Post-Traumatic Osteoarthritis
Organism Mus musculus
Experiment type Expression profiling by array
Summary Targeting MMP13 directly by RNA interference (RNAi) silenced MMP13 in a murine post-traumatic osteoarthritis (PTOA) and was found to have broad effects on overall joint health, including both the articular cartilage and surrounding hard and soft tissues. To further characterize the global impacts of targeted MMP13 inhibition, the mechanical loading mouse model was applied with samples were harvested at 4 weeks to capture an intermediate stage of disease. The nanoString nCounter Inflammation panel was used to broadly quantify gene expression of the knee joint samples (articular cartilage, meniscal, and synovial tissue). Abstract: Osteoarthritis (OA) is a debilitating and prevalent chronic disease, but there are no approved disease modifying OA drugs (DMOADs), only pharmaceuticals for pain management. OA progression, particularly for post-traumatic osteoarthritis (PTOA), is associated with inflammation and enzymatic degradation of the extracellular matrix. In particular, matrix metalloproteinase 13 (MMP13) breaks down collagen type 2 (CII), a key structural component of cartilage extracellular matrix, and consequently, matrix degradation fragments perpetuate inflammation and a degenerative cycle that leads to progressive joint pathology. Here, we tested extracellular matrix-binding MMP13 RNA interference (RNAi) nanoparticles (NPs) as a DMOAD. The retention approach pursued here deviates from the convention of targeting specific cell types (e.g., through cell surface receptors) and instead leverages a monoclonal antibody (mAbCII) that targets extracellular CII that becomes uniquely accessible in OA-damaged cartilage. CII monoclonal antibody-functionalized nanoparticles carrying small interfering ribonucleic acid (siRNA) (mAbCII-siNPs) create an in situ NP depot for retention and potent activity within OA joints. The mAbCII-siNPs loaded with MMP13 siRNA (mAbCII-siNP/siMMP13) potently suppressed MMP13 expression (95% silencing) in TNFα-stimulated chondrocytes in vitro and had higher binding to trypsin-damaged porcine cartilage than control NPs. In an acute mechanical injury mouse model of PTOA, mAbCII-siNP/siMMP13 achieved 80% reduction in MMP13 expression (p = 0.00231), whereas control siNP/siMMP13 achieved only 55% silencing. In a more severe, longer-term PTOA model, weekly mAbCII-siNP/siMMP13 treatment provided significant protection of cartilage integrity (0.45+/-.3 vs 1.6+/-.5 on the OARSI scale; p=0.0013) and overall joint structure (1.3+/-.6 vs 2.8+/-.2 on the Degenerative Joint Disease scale; p=0.0418), including reduction of osteophyte formation (siMMP13 vs siNEG: 0.088+/-0.074 vs 0.47+/-0.107 mm femoral osteophyte outgrowth; p<0.0001). Multiplexed gene expression analysis of 254 inflammation-related genes showed that MMP13 inhibition suppressed clusters of genes associated with tissue restructuring, angiogenesis, innate immune response, and proteolysis. Finally, in benchmarking studies, intra-articular mAbCII-siNPs better reduced OA disease progression relative to either one time or weekly treatment with the clinical gold standard steroid methylprednisolone. Here, we introduce the concept of anchoring to unique local extracellular matrix signatures to sustain retention and increase delivery efficacy of biologics with intracellular activity and also validates the promise of MMP13 RNAi as a DMOAD in a clinically-relevant therapeutic context.
 
Overall design Groups are either healthy mice or subjected to an acute PTOA model of noninvasive, repetitive joint loading by subjecting the knee joints of 8-week-old C57BL/6 mice to 500 cycles of compressive mechanical loading at 9N (adapted from Poulet B, et al. Arthritis and rheumatism. 2011. PubMed PMID: 20882669). This procedure was repeated five times per week over a period of four weeks. PTOA groups were either left untreated or treated MMP13-specific or negative control small interfering RNA (siRNA) loaded into collagen II-targeting antibodies conjugated to polymer nanopartiples (mAbCII-siNPs/siMMP13 or siNEG).
 
Contributor(s) Bedingfield SK, Duvall C
Citation(s) 34413494
NIH grant(s)
Grant ID Grant title Affiliation Name
R01 CA224241 NextGen RNAi Delivery to Breast Tumors for Selective mTORC2 Blockade Vanderbilt University Craig Lewis Duvall
R01 EB019409 Substrate Mediated siRNA Delivery from Scaffolds to Promote Wound Repair Vanderbilt University Craig Lewis Duvall
Submission date Mar 29, 2021
Last update date May 30, 2023
Contact name Sean K Bedingfield
Organization name Vanderbilt University
Department Biomedical Engineering
Street address 2301 Vanderbilt Place PMB 351826
City Nashville
State/province TN
ZIP/Postal code 37235-1826
Country USA
 
Platforms (1)
GPL27566 NanoString nCounter Mouse Inflammation Panel V2 (Mm-inflam-v2)
Samples (48)
GSM5216905 Joint_healthy_untreated_rep1
GSM5216906 Joint_healthy_untreated_rep2
GSM5216907 Joint_healthy_untreated_rep3
Relations
BioProject PRJNA718183

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE171031_RAW.tar 200.0 Kb (http)(custom) TAR (of RCC)
Processed data included within Sample table

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