Cindy Boer

Epigenomics in bone and cartilage disease | 45 1.2 [72, 80-82]. However, in general, the identity of regulated miRNAs varies widely across the studies and sometimes conflicting evidence is found. In addition, given the absence of replication across study outcomes and the small sample sizes, these studies should be considered as exploratory and further replication and validation is warranted. It is also to mention that circulating levels of miRNAs reflect processes in the whole body, most notably those of blood cells, and therefore miRNA signatures could be influenced by co‐morbid conditions and other circumstances (such as aging in general, low‐grade inflammation, etc.)[80]. Thus, published data are promising, but more work is needed before miRNAs can serve as robust diagnostic and prognostic tools in the clinic. Histones and Chromatin Structure in Skeletal Disorders Evidence is slowly being accumulated for a role of histone PTMs in chondrocyte and osteoblast differentiation, skeletal development, and the pathogenesis of OA and oste- oporosis[83-88]. There is a well‐established role for HATs and HDACs in chondrogen- esis, involving the regulation and function of Sox9 and its downstream targets. Sox9 is an essential regulator of chondrocyte differentiation and homeostasis[89]. The HDAC KDM4B mediates Sox9 activation by removing a repressive histone PTM (namely, meth- ylation of lysines 9 in histone 3; H3K9me3) from the Sox9 promoter region, which in turn triggers TGF‐β‐mediated chondrogenesis.[90] Regulation of downstream targets of Sox9 is also dependent of histone remodelers. The HDAC Sirt1 binds to the enhancer and promoter region of COL2A1 , which in turn recruits the HATs p300/CBP[91]. These form a complex with Sox9 at the COL2A1 promoter. By relaxing the chromatin structure near the COL2A1 promoter by P300/CBP through their HAT activity, Sox9 is able to ini- tiate COL2A1 expression[92, 93]. Recently, the HDAC KDM6B has also been suggested to regulate COL2A1 expression, possibly also by direct interaction with the promoter of COL2A1 [94]. Conversely, the HDAC ELF3 suppresses COL2A1 transcription by inhibiting the HAT activity of the Sox9/CBP complex[95, 96]. Many other histone remodelers are being implicated in osteoblast and chondro- cyte development[83, 97]. Recently, KDM6B, a HDAC, has been shown to be significant- ly increased in expression during cartilage development[94]. Also, identified through genome-wide association studies (GWAS), DOT1L , a histone lysine methyltransferase, might be involved in chondrocyte differentiation and homeostasis[98, 99]. The pro- teins that “read” the histone PTMs are also important for cell differentiation. Proteins from the bromodomain and extra‐terminal domain (BET) family recognize and bind to acetylated lysine on histones, forming a scaffold for protein complexes involved in gene transcription[100, 101]. The inhibition of BET proteins leads to a suppression of os-