Integrative MicroRNA and Proteomic Approaches Identify Novel Osteoarthritis Genes and Their Collaborative Metabolic and Inflammatory Networks

Abstract

BackgroundOsteoarthritis is a multifactorial disease characterized by destruction of the articular cartilage due to genetic, mechanical and environmental components affecting more than 100 million individuals all over the world. Despite the high prevalence of the disease, the absence of large-scale molecular studies limits our ability to understand the molecular pathobiology of osteoathritis and identify targets for drug development.Methodology/Principal FindingsIn this study we integrated genetic, bioinformatic and proteomic approaches in order to identify new genes and their collaborative networks involved in osteoarthritis pathogenesis. MicroRNA profiling of patient-derived osteoarthritic cartilage in comparison to normal cartilage, revealed a 16 microRNA osteoarthritis gene signature. Using reverse-phase protein arrays in the same tissues we detected 76 differentially expressed proteins between osteoarthritic and normal chondrocytes. Proteins such as SOX11, FGF23, KLF6, WWOX and GDF15 not implicated previously in the genesis of osteoarthritis were identified. Integration of microRNA and proteomic data with microRNA gene-target prediction algorithms, generated a potential “interactome” network consisting of 11 microRNAs and 58 proteins linked by 414 potential functional associations. Comparison of the molecular and clinical data, revealed specific microRNAs (miR-22, miR-103) and proteins (PPARA, BMP7, IL1B) to be highly correlated with Body Mass Index (BMI). Experimental validation revealed that miR-22 regulated PPARA and BMP7 expression and its inhibition blocked inflammatory and catabolic changes in osteoarthritic chondrocytes.Conclusions/SignificanceOur findings indicate that obesity and inflammation are related to osteoarthritis, a metabolic disease affected by microRNA deregulation. Gene network approaches provide new insights for elucidating the complexity of diseases such as osteoarthritis. The integration of microRNA, proteomic and clinical data provides a detailed picture of how a network state is correlated with disease and furthermore leads to the development of new treatments. This strategy will help to improve the understanding of the pathogenesis of multifactorial diseases such as osteoarthritis and provide possible novel therapeutic targets.

MiR‐29b‐3p promotes chondrocyte apoptosis and facilitates the occurrence and development of osteoarthritis by targeting PGRN

“…Over the past decade, mounting evidence shows that a variety of miRNAs was involved in the occurrence and development of OA. It was identified that the expression of miR‐483, miR‐22, miR‐377, miR‐103, miR‐16, miR‐223, miR‐30b, miR‐23b and miR‐509 was up‐regulated in osteoarthritic cartilage of human knee join compared to normal cartilage, but the expression of miR‐29a, miR‐140, miR‐25, miR‐337, miR‐210, miR‐26a and miR‐373 was down‐regulated 22. Dimitrios Iliopoulos et al .…”

Serum miRNA Signatures Are Indicative of Skeletal Fractures in Postmenopausal Women With and Without Type 2 Diabetes and Influence Osteogenic and Adipogenic Differentiation of Adipose Tissue–Derived Mesenchymal Stem Cells In Vitro

“…miRNAs have been reported to master-regulate diverse physiologic cellular functions including differentiation, apoptosis, (55) oxidative stress, (56) and remodeling. (57) Altered miRNA serum profiles were also described for many pathologic processes, including diverse types of cancer, (58,59) and chronic diseases such as osteoarthritis, (60,61) coronary heart disease, (62) and T2D. (22) However, to our knowledge this is the first study that has investigated the expression profiles of serum miRNAs in T2D postmenopausal women with respect to their history of fragility fractures.…”

Control of EVI-1 oncogene expression in metastatic breast cancer cells through microRNA miR-22

“…The role of let-7f in tumorigenesis and metastasis is well known (O'Day and Lal, 2010); therefore, we did not place much emphasis on this miRNA. However, miR-22 is a relatively new player and has been linked to cellular metabolism and chronic inflammatory diseases such as osteoarthritis (Iliopoulos et al, 2008). Normal mammary stem cells express high levels of miR-22 and little-to-no let-7; however, during progressive differentiation, the expression of miR-22 decreases and expression of let-7 family members is induced (Ibarra et al, 2007).…”

“…However, it appears that the role of miR-22 is different in a metastasis setting. miR-22 targets the extracellular environment via matrix metalloproteinases and interleukins and thus has a function in inflammatory conditions (Iliopoulos et al, 2008). Putative downstream targets of miR-22 include ERBB3, CDC25C, EVI-1, SIRT1, AKT3, SATB2, HDAC4, CBL, peroxisome proliferator activated receptor a and BMP7.…”