Cindy Boer

Epigenomics in bone and cartilage disease | 43 1.2 performed in a collaborative study examining the relationship with BMD in a total of 5,515 participants[60]. However, this did not result in robustly associated CpGs, sug- gesting that blood might not be the correct tissue to study the epigenomic features in relation to bone phenotypes. In contrast, another small study examining 22 controls versus 22 osteoporotic women (defined by low BMD) identified a large number of dif- ferentially methylated sites[61]. Importantly, this study lacked replication and adjust- ment of several important possible confounders, such as cell counts and BMI. Non‐coding RNAs in Skeletal Disorders Among ncRNAs, miRNAs have beenmost extensively studied in relation to bone and car- tilage diseases. More than 35 miRNAs modulate the differentiation of osteoblast precur- sors in vitro, through various mechanisms, including targeting master regulators such as RUNX2 (see recent reviews)[62-64]. A few of them have demonstrated effects on bone in animal models in vivo and may be involved in osteoclast‐osteoblast communi- cation. For example, osteoclast‐derived exosomal miR‐214‐3p inhibits osteoblast activi- ty in vitro and reduces bone formation in vivo[65]. The miR‐34 family and miR‐214 also tend to have a negative influence on bone formation[66]. On the other hand, miR‐2861 and miR‐29a stimulate bone formation. Interestingly, they target HDACs, thus illustrat- ing the interactions between different layers of epigenetic marks[67]. As with the os- teoblastic lineage, several miRNAs influence osteoclast differentiation in vitro. Some of them have been validated in vivo. For instance, miR‐503, which targets RANKL, and miR‐34a inhibit bone resorption in animal models, whereas miR‐148a tends to stimu- late resorption[62, 64, 68]. Some miRNAs are abundant in cartilage and appear to be important for the regulation of metalloproteases, toll‐like receptor signalling, and other genes involved in catabolic pathways[69]. A recent review of 57 studies about miRNA expression in cartilage revealed 46 differentially expressed miRNAs in OA, which were involved in autophagy, chondrocyte homeostasis, and degradation of the extracellular matrix[70]. For instance, miR‐140 is involved in the pathogenesis of OA by regulating, at least in part, MMP13 and ADAMTS5. miR‐140 is downregulated in OA cartilage and the intra‐articular injection of miRNA‐140 alleviates OA progression in rats[71]. The potential role of other miRNAs in OA pathogenesis has been recently reviewed[42, 72]. In a few cases, their effects have been validated by gain‐of‐function or loss‐of‐function experiments in vivo ( Table 2 ).