Synovium-Derived MicroRNAs Regulate Bone Pathways in Rheumatoid Arthritis
Authors
Maeda, YukikoFarina, Nicholas H.
Matzelle, Melissa M.
Fanning, Paul J.
Lian, Jane B.
Gravallese, Ellen M.
UMass Chan Affiliations
Department of Orthopedics and Physical RehabilitationDepartment of Medicine, Division of Rheumatology
Document Type
Journal ArticlePublication Date
2017-03-01Keywords
bonemicroRNA
osteoblast
rheumatoid arthritis
synovium
Cell Biology
Musculoskeletal Diseases
Rheumatology
Metadata
Show full item recordAbstract
Articular bone erosion in rheumatoid arthritis (RA) is mediated by the interaction between inflammation and pathways regulating bone metabolism. Inflammation promotes osteoclastogenesis and also inhibits osteoblast function, further contributing to the persistence of erosions. MicroRNAs (miRNAs) are important regulators of skeletal remodeling and play a role in RA pathogenesis. We therefore determined the expression of miRNAs in inflamed synovial tissue and the role they play in pathways regulating osteoblast and osteoclast function. Using the serum transfer mouse model of RA in C57BL/6 mice, we performed Fluidigm high-throughput qPCR-based screening of miRNAs from nonarthritic and arthritic mice. Global gene expression profiling was also performed on Affymetrix microarrays from these same synovial samples. miRNA and mRNA expression profiles were subjected to comparative bioinformatics. A total of 536 upregulated genes and 417 downregulated genes were identified that are predicted targets of miRNAs with reciprocal expression changes. Gene ontology analysis of these genes revealed significant enrichment in skeletal pathways. Of the 22 miRNAs whose expression was most significantly changed (p < 0.01) between nonarthritic and arthritic mice, we identified their targets that both inhibit and promote bone formation. These miRNAs are predicted to target Wnt and BMP signaling pathway components. We validated miRNA array findings and demonstrated that secretion of miR-221-3p in exosomes was upregulated by synovial fibroblasts treated with the proinflammatory cytokine TNF. Overexpression of miR-221-3p suppressed calvarial osteoblast differentiation and mineralization in vitro. These results suggest that miRNAs derived from inflamed synovial tissues may regulate signaling pathways at erosion sites that affect bone loss and potentially also compensatory bone formation.Source
J Bone Miner Res. 2017 Mar;32(3):461-472. doi: 10.1002/jbmr.3005. Epub 2016 Oct 28. Link to article on publisher's siteDOI
10.1002/jbmr.3005Permanent Link to this Item
http://hdl.handle.net/20.500.14038/28975PubMed ID
27676131Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1002/jbmr.3005