Identification of DNA methylation changes associated with disease progression in subchondral bone with site-matched cartilage in knee osteoarthritis.

Yanfei Zhang,Yozo Katsuragawa,Naoshi Fukui,Shiro Ikegawa,Mitsunori Yahata,Toshiyuki Tashiro,Ming Ta Michael Lee

doi:10.1038/srep34460

Abstract

Subchondral bone plays a key role in the development of osteoarthritis, however, epigenetics of subchondral bone has not been extensively studied. In this study, we examined the genome-wide DNA methylation profiles of subchondral bone from three regions on tibial plateau representing disease progression using HumanMethylation450 BeadChip to identify progression associated DNA methylation alterations. Significant differential methylated probes (DMPs) and differential methylated genes (DMGs) were identified in the intermediate and late stages and during the transition from intermediate to late stage of OA in the subchondral bone. Over half of the DMPs were hyper-methylated. Genes associated with OA and bone remodeling were identified. DMGs were enriched in morphogenesis and development of skeletal system, and HOX transcription factors. Comparison of DMGs identified in subchondral bone and site-matched cartilage indicated that DNA methylation changes occurred earlier in subchondral bone and identified different methylation patterns at the late stage of OA. However, shared DMPs, DMGs and common pathways that implicated the tissue reparation were also identified. Methylation is one key mechanism to regulate the crosstalk between cartilage and subchondral bone.

Highlights

Subchondral bone plays a key role in the development of osteoarthritis, epigenetics of subchondral bone has not been extensively studied
During OA progression, the architecture and components of the subchondral bone are modified through the processes of remodeling by osteoblasts and osteoclasts to adapt to the altered mechanical loading[2]
Osteocytes and cell lines have confirmed that methylation in promoter regions or the vicinity of transcription start sites of ALPL, SOST, RANKL and OPG, which participate in OA, were associated with their low expression

Summary

Introduction

Subchondral bone plays a key role in the development of osteoarthritis, epigenetics of subchondral bone has not been extensively studied. Osteocytes and cell lines have confirmed that methylation in promoter regions or the vicinity of transcription start sites of ALPL, SOST, RANKL and OPG, which participate in OA, were associated with their low expression. Demethylation of these genes could increase their expression[4,5,6], suggesting an important role of DNA methylation in osteogenesis. We aimed to evaluate genome-wide DNA methylation profiles in subchondral bone and identify the differential methylated genes (DMGs) and pathways associated with disease progression. DMGs identified from the subchondral bone and cartilage were analyzed and compared to evaluate the common pathways and interactions during OA progression

Objectives

Methods

Results

Conclusion