title: Stage-Specific miRs in Chondrocyte Maturation: Differentiation-Dependent and Hypertrophy-Related miR Clusters and the miR-181 Family.
abstract: Human mesenchymal stromal cells (hMSC) differentiating toward the chondrogenic lineage recapitulate successive phases of embryonic chondrocyte maturation developing from progenitor cells to hypertrophic chondrocytes. Osteoarthritic cartilage is characterized by an alteration in chondrocyte metabolism and upregulation of hypertrophic differentiation markers. A number of studies point toward a functional role for microRNAs (miRs) in controlling chondrocyte differentiation and development of osteoarthritis (OA). However, information on miRs that may regulate a specific phase of chondrocyte maturation, especially hypertrophy, is lacking. We here aimed to unravel miR profiles modulated during chondrogenesis of hMSC to obtain new differentiation markers and potential new targets relevant for differentiation outcome and OA development. hMSC were subjected to transforming growth factor-β (TGF-β)-driven chondrogenesis and miR profiles were determined by microarray analysis at distinct developmental time points. Expression of selected miRs was compared to cultures lacking chondrogenesis and to redifferentiated nonhypertrophic articular chondrocytes. Among 1349 probed miRs, 553 were expressed and 169 (31%) were significantly regulated during chondrogenesis. Hierarchical clustering identified specific miR expression patterns representative for MSC, prechondrocytes, chondroblasts, chondrocytes, and hypertrophic chondrocytes, respectively. Regulation of miR-181 family members allowed discrimination of successive differentiation stages. Levels of several miRs, including miR-23b, miR-140, miR-181, and miR-210 positively correlated with successful chondrocyte formation. Hypertrophic MSC-derived chondrocytes and nonhypertrophic articular chondrocytes showed differential expression of miR-181a, miR-210, and miR-31, but not miR-148a implicated in COL10A1-regulation. We conclude that the here identified stage-dependent miR clusters may have imperative functions during chondrocyte differentiation providing novel diagnostic tools and targets of potential relevance for OA development.
authors.affiliation: 1 Research Centre for Experimental Orthopaedics, Orthopaedic University Hospital Heidelberg , Heidelberg, Germany .
authors.forename: Jessica
authors.initials: J
authors.lastname: Gabler
authors.affiliation: 1 Research Centre for Experimental Orthopaedics, Orthopaedic University Hospital Heidelberg , Heidelberg, Germany .
authors.forename: Martin
authors.initials: M
authors.lastname: Ruetze
authors.affiliation: 1 Research Centre for Experimental Orthopaedics, Orthopaedic University Hospital Heidelberg , Heidelberg, Germany .
authors.forename: Katharina L
authors.initials: KL
authors.lastname: Kynast
authors.affiliation: 2 Department of Orthopaedic and Trauma Surgery, Orthopaedic University Hospital Heidelberg , Heidelberg, Germany .
authors.forename: Tobias
authors.initials: T
authors.lastname: Grossner
authors.affiliation: 1 Research Centre for Experimental Orthopaedics, Orthopaedic University Hospital Heidelberg , Heidelberg, Germany .
authors.forename: Solvig
authors.initials: S
authors.lastname: Diederichs
authors.affiliation: 1 Research Centre for Experimental Orthopaedics, Orthopaedic University Hospital Heidelberg , Heidelberg, Germany .
authors.forename: Wiltrud
authors.initials: W
authors.lastname: Richter
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002454:Cell Differentiation; D019902:Chondrocytes / Q000378:metabolism* / Q000473:pathology; D024121:Collagen Type X / Q000096:biosynthesis*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D006984:Hypertrophy; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis*; D008875:Middle Aged; D010003:Osteoarthritis / Q000378:metabolism* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D024121:Collagen Type X; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D016212:Transforming Growth Factor beta