SnoRNA signatures in cartilage ageing and osteoarthritis

Mandy J Peffers,Peter Z Feczko,Tim J M Welting,Panagiotis Balaskas,Marjolein M Caron,Alzbeta Chabronova,Pieter J Emans,Andy Cremers,Yongxiang Fang,Philip Dyer

doi:10.1038/s41598-020-67446-z

Mandy J Peffers, Peter Z Feczko + Show 8 more

Open Access

https://doi.org/10.1038/s41598-020-67446-z

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Abstract

Osteoarthritis presents as a change in the chondrocyte phenotype and an imbalance between anabolic and catabolic processes. Age affects its onset and progression. Small nucleolar RNAs (SnoRNAs) direct chemical modification of RNA substrates to fine-tune spliceosomal and rRNA function, accommodating changing requirements for splicing and protein synthesis during health and disease. Articular cartilage from young, old and OA knees was used in a microarray study to identify alterations in snoRNA expression. Changes in snoRNAs in osteoarthritis-like conditions were studied in chondrocytes using interleukin-1 and osteoarthritic synovial fluid. SNORD26 and SNORD96A knockdown and overexpression were undertaken using antisense oligonucleotides and overexpression plasmids. We identified panels of snoRNAs differentially expressed due to ageing (including SNORD96A, SNORD44) and osteoarthritis (including SNORD26 and SNORD116). In vitro experiments using osteoarthritis-like conditions affected snoRNA expression. Knockdown or overexpression of SNORD26 or SNORD96A resulted in changes in chondrogenic, hypertrophic, rRNA and osteoarthritis related gene expression. We demonstrate that snoRNA expression changes in cartilage ageing, and osteoarthritis and in osteoarthritis-like conditions, and when the expression of these snoRNAs is altered this affects chondrogenic and hypertrophic gene expression. Thus, we propose an additional dimension in the molecular mechanisms underlying cartilage ageing and osteoarthritis through the dysregulation of snoRNAs.

Highlights

Osteoarthritis presents as a change in the chondrocyte phenotype and an imbalance between anabolic and catabolic processes
We have reported that the expression of the non-canonical snoRNA RMRP is regulated during chondrogenic differentiation and regulates chondrocyte hypertrophy[29]
The maintenance of the extracellular matrix (ECM) demands a sufficient number of functional ribosomes to translate cartilage ECM-related mRNAs into proteins and ribosome functionality may adapt to OA chondrocyte phenotypic changes

Summary

Introduction

Osteoarthritis presents as a change in the chondrocyte phenotype and an imbalance between anabolic and catabolic processes. We identified panels of snoRNAs differentially expressed due to ageing (including SNORD96A, SNORD44) and osteoarthritis (including SNORD26 and SNORD116). Knockdown or overexpression of SNORD26 or SNORD96A resulted in changes in chondrogenic, hypertrophic, rRNA and osteoarthritis related gene expression. We demonstrate that snoRNA expression changes in cartilage ageing, and osteoarthritis and in osteoarthritis-like conditions, and when the expression of these snoRNAs is altered this affects chondrogenic and hypertrophic gene expression. Human 18S, 5.8S and 28S rRNAs contain at least 110 individual 2′O-ribose methylated and 100 pseudouridylated n ucleotides[5] These post-transcriptional modifications (PTMs) fine-tune translational characteristics of the ribosome. The researchers alluded that rRNA modifications play an fundamental role in vertebrate development[7] This was recently emphasised by a study showing important dynamics in rRNA ribose methylation and snoRNA expression during mouse development[8]. Others have identified SNORD38 and SNORD48 as potential non-age-dependant serum biomarkers for OA progression following cruciate ligament injury[23]

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