Why is epigenetics important in understanding the pathogenesis of inflammatory musculoskeletal diseases?

In its widest sense, the term epigenetics describes a range of mechanisms in genome function that do not solely result from the DNA sequence itself. These mechanisms comprise DNA and chromatin modifications and their associated systems, as well as the noncoding RNA machinery. The epigenetic apparatus is essential for controlling normal development and homeostasis, and also provides a means for the organism to integrate and react upon environmental cues. A multitude of functional studies as well as systematic genome-wide mapping of epigenetic marks and chromatin modifiers reveal the importance of epigenomic mechanisms in human pathologies, including inflammatory conditions and musculoskeletal disease such as rheumatoid arthritis. Collectively, these studies pave the way to identify possible novel therapeutic intervention points and to investigate the utility of drugs that interfere with epigenetic signalling not only in cancer, but possibly also in inflammatory and autoimmune diseases.


Introduction
Doubtlessly, the fi eld of epigenetics has rapidly evolved over the last decades -a quick literature survey shows 18 PubMed entries for 1975 to 1995, >400 entries for the following 10 years and >2,000 entries from 2006 to 2010. Importantly, the defi nition of epigenetics now extends signifi cantly from its initial meaning into other disciplines and encompasses wide research areas within genetics, genomics, molecular biology and medicine (including, for example, epidemiology and pathology) (see Figure 1). Th e term epigenesis originally coined by Waddington over 50 years ago was introduced in a develop mental biology context to describe how genotypes give rise to diff erent phenotypes [1], a view that is fundamentally diff erent from the defi nition of 'the heritable transmission of phenotype without a change in the underlying DNA sequence' that is now widely in use. Over the years, however, this interpretation of epigenetics has found signifi cant alterations -in fact, there now appears to be no uniform consensus defi nition [2,3]. Whereas developmental biologists emphasise the transgenerational heritability aspect of epigenetics (that is, the necessity to stably transmit epigenetic modifi cations to achieve a pheno type), many scientists nowadays use the term epigenetic in a less constrained manner. In this way they relate almost any covalent chromatin modifi cation with under lying general events that are considered DNAtemplated processes and thus include transcription, DNA repair or genome stability [4].
Irrespective of this semantic debate, this review aims to describe the various major systems that modify chroma tin components as well as DNA to accomplish gene regulation and functional chromatin states. In this overview, epigenetics is used in its widest sense -that is, epigenetics includes a discussion of DNA and chromatin modifi cations as well as the area of noncoding RNA, known to play key roles in imprinting, gene regulation and silencing. Th e article proposes that a better understanding of these epigenetic mechanisms and their eff ects will lead to an appreciation of their potential roles in musculoskeletal and infl ammatory disease pathologies, and, fi nally, might pave the way to novel possible therapeutic intervention strategies.

What is the biochemical basis of epigenetics?
Chromatin is a highly organised and dynamic protein-DNA complex consisting of DNA, histones and nonhistone proteins. Within this framework, epigenetic mechanisms alter the accessibility of DNA by modifi cation or rearrangement of nucleosomes, as well as through a plethora of post-translational chemical modifi cations of Abstract In its widest sense, the term epigenetics describes a range of mechanisms in genome function that do not solely result from the DNA sequence itself. These mechanisms comprise DNA and chromatin modifi cations and their associated systems, as well as the noncoding RNA machinery. The epigenetic apparatus is essential for controlling normal development and homeostasis, and also provides a means for the organism to integrate and react upon environmental cues. A multitude of functional studies as well as systematic genome-wide mapping of epigenetic marks and chromatin modifi ers reveal the importance of epigenomic mechanisms in human pathologies, including infl ammatory conditions and musculoskeletal disease such as rheumatoid arthritis. Collectively, these studies pave the way to identify possible novel therapeutic intervention points and to investigate the utility of drugs that interfere with epigenetic signalling not only in cancer, but possibly also in infl ammatory and autoimmune diseases.
chromatin proteins such as histones and DNA itself (see below). In addition to the intricate interactions that occur between chromatin proteins and DNA, the noncoding RNA machinery is included to be epigenetic -as part of a complex network entangled with chromatin and DNA modifi cation systems, which alter and critically control gene expression patterns during development, homeostasis and disease [5,6].
Epigenomics -that is, the genome-wide study of epigenetics -is made feasible using recently developed nextgeneration sequencing platforms and, importantly, has provided an insight into genome architecture that was not anticipated by researchers a decade ago when comple tion of the fi rst genome-sequencing projects was accomplished. Following this development, the recent large-scale chromatin profi ling and interaction mapping across many diff erent cell types and their functional states carried out by the ENCODE (Encyclopedia of DNA Elements) consortium has already resulted in functional annotation of about 80% of the human genome, the vast majority of which is nonprotein coding. Th is largescale collaborative project has revealed common regulatory elements, their func tional interactions as well as chromatin state dynamics leading to an unprecedented, detailed view of genome biology [7][8][9][10] with clear implications and novel avenues in understanding of human disease (see below).
An important aspect in the epigenetic concept is that the local chromatin structure is of critical importancefor example, accessible chromatin (that is, as found in euchromatin) allows gene-regulatory proteins such as trans cription factors or remodelling complexes to interact with their cognate binding sites within the regulatory regions of genes, such as proximal promoters, enhancers or silencers [7,9]. Modifi cation systems (so-called writers and erasers of chromatin marks) that covalently alter specifi c residues of chromatin proteins play a pivotal role in this process (Table 1). Equally important, the distinct chromatin modifi cations or marks can act as beacons to recruit specifi cally recognition domains and components (readers) of transcriptional complexes, which thus serve as the eff ectors of the modifi cation. In this complex and interdependent manner (defi ned as the histone code) [11], chromatin modifying systems exert control of global and local gene activation. In addition, chromatin capture methods have revealed the critical importance of nuclear architecture and long-range chromatin interactions in regulation of concerted gene programmes [12] -this is illustrated, for example, by the murine Th 2 cytokine locus where gene regions are folded into connected dynamic DNA loop structures anchored by AT-rich sequence binding proteins [13].

DNA methylation in an epigenetic context
Among the epigenetic mechanisms regulating gene expression, DNA methylation is by far the most studiedalthough, it is probably fair to say, still incompletely under stood. In vertebrate genomes, DNA methylation mostly occurs at the 5' position on cytosine bases and largely in the context of CpG islands. Th is cytosine modifi cation critically controls genome functions by silencing of genes (see below), and has a function in controlling centromeric stability and probably suppresses the expression and mobility of transposable elements [14]. Because 5-methylcytosine can be spontaneously deaminated (by replacing nitrogen with oxygen) to thymidine, CpG sites are frequently mutated and thus become rare in the genome. Epigenetic changes of this type thus have the potential to directly contribute to permanent genetic mutations.
About 70 to 80% of annotated gene promoters are associated with CpG islands, which are usually unmethylated, but a substantial amount of cytosine methylation is also found in gene bodies and intergenic sequences, the function of which is beginning to emerge [15]. Importantly, cell-type specifi c DNA methylation profi les appear to vary more frequently at intergenic sequences compared with annotated gene promoters [9]. Th ese sites of diff erential methylation them selves might regulate the activity of distant enhancers [16] or the transcription of noncoding RNAs and uncharacterised transcripts [17,18]. Methylation of CpG promoter sites is associated with stable silencing of gene expression, and aberrant methyla tion patterns -for example, hypermethylation of tumour suppressor genes or hypomethylation of oncogenes -are now recognised as hallmarks of cancer [19][20][21][22][23]. Silencing through DNA methylation is achieved by preventing the binding of distinct transcription factors, or by recruiting methyl-binding proteins, thereby generating a repressed chro matin environment. Th ese patterns of DNA methylation can be stably propagated during cell division, which makes this process a paradigm for true epigenetic regu la tion. Accordingly, these DNA modifi cations can mediate long-lasting changes in gene expression even when the initial triggering signal has disappeared.
DNA methylation patterns are known to be established and modifi ed in response to environmental factors by a complex interplay of at least three independent DNA methyltransferases, DNMT1, DNMT3A and DNMT3B [24] -hence making DNA methylation a prime candidate for linking environmental cues and disease. Interestingly, a recent epigenome-wide DNA methylation study among >300 rheumatoid arthritis (RA) patients identifi ed several diff erentially methylated regions within the MHC region, suggesting a possible link between genetic predisposition and epigenetic modifi cation and function in RA [25]. DNA methylation patterns have long been known to undergo signifi cant changes during fertilisation and embryogenesis, highlighting the existence of systems that can revert and erase DNA methylation [24]. Once established in diff erentiated cells, DNA methylation is considered stable; however, recent studies reveal that it appears to also be subject to demethylation (that is, reversal of biological eff ect) in specifi c instances, involving several incompletely charac ter ised candidate mechanisms (that is, methylcytosine hydroxylation, DNA glycosylation, base excision repair and deaminases), all of which have been shown to play important roles in genome biology and disease (reviewed in [24]).

Histone modifi cations are important elements of the epigenomic landscape
In addition to the modifi cations described above for DNA, post-translational modifi cations of N-terminal, un structured tails of histone proteins have now been recognised as key components in the regulation and signalling of functional states of the epigenomic landscape. For example, trimethylated lysine 9 of histone 3 (H3K9me3) indicates heterochromatic or repetitive regions, whereas H3K4me3 marks regulatory elements associated with active promoters or transcription start sites and H3K27me3 marks those for developmentally repressed genes [9].
At present, several classes of histone modifi cations and their respective enzymatic modifi cation systems have been identifi ed (Table 1) [26]. Amongst their epigenetic substrate marks, lysine and arginine modifi cations are probably the best studied: acetylation and methylation of lysine residues, as well as methylation of arginine [26][27][28].
Whereas acetylation of histone tails is correlated with gene activation [26], the infl uence of histone methylation on regulating gene transcription depends on the exact residue methylated and the number of added methyl groups, both for arginine and lysine residues [28]. Th e involvement of histone modifi cations in regulation of key aspects in musculoskeletal biology -for example, in infl am mation [29][30][31][32][33] or diff erentiation [34][35][36] -has recently been established. Th e best understood systems of histone modifi cations that potentially allow transmission of stable heritable marks through cell divisions comprise methylation of H3K9 (HP1, heterochromatin establishment) and H3K27 and H3K4 (repression and activation of genes through polycomb and trithorax complexes, respectively) [37,38].
Importantly, histone modifi cations and DNA methylation act in concert with respect to gene regulation because both activities are functionally linked [39]. One should state that modifi cations of histone residues are the best studied reactions, but constitute only the tip of the iceberg of nuclear mechanisms regulating chromatin function since many reader binding specifi cities or enzymatic activities have not yet been elucidated. Furthermore, many of the writers and erasers also modify other chromatin-associated proteins such as key transcription factors -including, for example, p53, retinoblastoma or NF-κB [40][41][42][43] -and thus critically control gene transcription programmes and cell-fate decisions.

Noncoding RNAs contribute to epigenetic mechanisms
Over the last decade it has become apparent that the nonprotein coding fraction of the human genome is of critical importance for homeostasis and disease, as discussed in greater detail elsewhere [5,6]. Th ose noncoding RNAs are currently divided into several classes (transcribed ultraconserved regions, small nucleolar RNAs, PIWI interacting RNAs, large intergenic noncoding RNAs, long noncoding RNAs and miRNAs) based on their length, as well as their processing and eff ector mechanisms [6]. Whereas the most studied class of miRNAs are ~22 base long ribonucleotide sequences that target complementary untranslated regions of mRNAs, directing them for degradation in the RNA-induced silencing complex, or regulate their translation, other noncoding RNA types have diff erent or less understood mechanisms of action. Small nucleolar RNAs (60 to 300 bp size) are involved in ribosomal RNA modifi cations, the PIWI interacting RNAs (24 to 30 bp size) interact with PIWI proteins that are critical for genome stability regulation (for example, heterochromatin formation), and large intergenic RNAs and long noncoding RNAs (>200 bp size) are found in chromatin complexes.
Several of the noncoding RNA classes are considered part of the epigenetic machinery due to their critical involvement in epigenetic phenomena. For example, long noncoding RNAs can recruit chromatin remodelling complexes to specifi c loci, and are involved in DNA methy lation and other chromatin modifi cations. Th e impor tance of long noncoding RNAs is illustrated through their complex interactions -for example, with the HOX gene cluster, where hundreds of long noncoding RNAs regulate in a specifi c temporal and spatial manner chromatin accessibility and recruitment of histone modifi cation systems and RNA polymerase. Th ese noncoding RNA-chromatin complexes are furthermore central to X-chromosome inactivation and imprinting.
Much of the current work in this fi eld has been directed towards understanding of the miRNA system, and in particular several of the miRNAs have been shown to play key roles in disease [6]. However, the recurring question for the cause or consequence relationships of noncoding RNA systems is largely unanswered. Whereas the involvement in cancer biology is well studied, their role in other diseases such as infl ammatory conditions like RA is less understood and is only beginning to emerge. Amongst the miRNAs, some such as miR21, miR148a, miR155 or mi146a (and others) have been linked to infl ammatory disease and autoimmunity [44][45][46][47][48]. Importantly, poly morphisms in target regions (for example, the 3' UTR of IL-1 receptor-associated kinase 1) of noncoding RNAs such as miR146 might contribute to RA suscepti bility [49], highlighting the inter play of genetic and epigenetic mechanisms in disease. Taken together, the fi eld of noncoding RNAs is certainly in its infancy, and future research will further clarify its role in immunity and infl ammation, and ultimately will have to prove its therapeutic utility.

Reversibility of chromatin modifi cation and inheritance of phenotypes
Th e contemporary defi nition of epigenetics that describes mechanisms to produce 'stable, heritable phenotypes that result from chromosomal changes without alteration in DNA sequence' implies a stably stored sort of memory at a molecular level that is copied and maintained during subsequent cell divisions and is independent of the initiating stimulus.
In contrast to genetic lesions, epigenetic modifi cations on DNA and histones are reversible, which is illustrated by the activities of the various enzyme systems that are operative in maintaining the epigenomic signatures (cf. Table 1). For example, histone lysine acetyltransferases are counteracted by histone lysine deacetylases (histone deacetylases (HDACs)) in establishing histone acetylation modifi cations at lysine residues in the N-terminal tails. Similarly, histone lysine methyltransferases catalyse the S-adeno syl methionine-dependent methylation of lysine residues in histone and other chromatin proteins in a sequence and methylation state-specifi c manner -these marks can be removed by the recently discovered lysine demethy lases (formerly known as histone demethylases) in establishing histone methylation modifi cations. Th ese opposing activities thus constitute a switch mechanism between functional states -for example, changing between the acetylated (active transcription) and trimethy lated (repressed) state of H3K9 must involve the eraser activities described above. Th ere is also no doubt that active DNA demethylation plays a role, for example, in myeloid cell development. Interestingly, a recent study identifi ed diff erentially methylated regions in postmitotic cells as shown in monocyte cultures diff eren tiating to dendritic cell or macrophage populations [50]. Transmission of epigenetic and genetic states (for example, DNA methylation) vary considerably, with an error rate of 1 in 10 6 (DNA sequence) as compared with 1 in 10 3 (DNA modifi cation) [51]. Consequently, epigenetic signatures and marks diff er fundamentally from genetic lesions by showing a stochastic manifestation and often incomplete distribu tion, and are in principle (at least partially) reversible. Although much still needs to be learned in terms of biological and clinical signifi cance of the reversible nature of these epigenetic modifi cations, it does make the chromatin-modifying enzymes possible therapeutic targets as discussed in some detail further below.

How can epigenetics further our understanding of human disease?
For most autoimmune diseases, genetic evidence from monozygotic and dizygotic twin studies show concordance rates below 50%, suggesting that additional mechanisms exist which potentially link individual susceptibility and environmental factors such as lifestyle (for example, smoking or stress), infection or xenobiotic exposure [52][53][54][55]. Genome-wide association studies (GWASs), for example, have provided a wealth of possible genetic factors contributing to the phenotypic diversity of syndromes such as RA and ankylosing spondylitis [56,57] . Genes identifi ed by searches for common genetic variants associated with disease have been highly productive in both RA and ankylosing spondylitis, and the eff ect of targeting the products of such contributory genes may be dispro por tionately greater than the apparent contribution to syndrome susceptibility.
Furthermore, gene associations have thus far failed to explain the heterogeneity of clinical features and response to targeted therapies across patient subgroups. Th is concept of missing heritability might be (at least in part) explained by several mechanisms such as unmapped common variants, rare variants, gene-gene interaction or, not unlikely, epigenetic mechanisms. Although genetic mutations in the epigenetic machinery (that is, readers, writers, erasers) occur -for instance, mutations in the DNA methyltransferase DNMT3B in immunodefi ciency/ centromeric instability/facial anomalies syndrome, or in Rett syndrome showing mutations in the methyl-CpG binding protein 2 -it is unlikely that monogenic lesions in epigenetic eff ector mechanisms contribute significantly to complex multifactorial human autoimmune disease such as RA. Many of the regions identifi ed in GWAS do not coincide with coding regions, however, but overlap with functional regulatory regions such as enhancers or transcription start sites identifi ed in the ENCODE project [7,9]. For example, 11 out of 57 SNPs identifi ed in RA GWASs overlap with transcription factor binding sites such as NF-κB [9]. In addition, risk loci such as the MHC cluster could be targeted by epigenetic modifi cation such as DNA methylation [25].
Epigenetics might also link environmental risk factors with genetic variation. Importantly, the epigenome itself is subject to environmental infl uences, as documented in multiple instances [58][59][60][61], and thus could act in concert with genetic variation to explain phenotypic variation and plasticity [62,63].
Among chronic infl ammatory diseases, RA has the highest prevalence in the western world and is a chronic and progressive infl ammatory disease. In RA, for example, the concordance of disease occurrence and progression in identical twins is only 10%, clearly indicating that environmental and/or epigenetic factors are involved both in induction (where smoking is the biggest environmental risk) and progression of disease [64]. Of note, a correlation between smoking and hypo methy lation of a CpG motif in the IL-6 promoter and resulting increased cytokine levels was established in a recent study among RA and chronic periodontitis patients [65]. Th is correlation indicates that a causal environ mental disease trigger could indeed lead to a change in cytokine profi le, although the connecting epigenetic mechanism in this relationship needs to be further defi ned.
Th e pathogenesis of disease in RA is attributed to the production of proinfl ammatory cytokines from activated cells that infi ltrate the synovial tissues from the blood (T cells, macrophages, plasma cells) together with resident cell types (fi broblasts and endothelium). Multiple studies addressing chromatin and DNA modifi cations in several autoimmune diseases (for reviews see [66][67][68]) have clearly shown that tissue-specifi c epigenetic modifications play a role in autoimmune disease. For example, DNA methylation in RA is impaired in peripheral blood mononuclear cells [69], and particularly in CD4 + T cells, rendering them more autoreactive. Th is impairment has been associated with decreased levels of DNA methyltransferases in senescent CD4 + CD28 -T cells [70].
In RA peripheral blood mononuclear cells, demethy lation of a single CpG in the IL-6 promoter region increased the production of this proinfl ammatory cytokine [71]. In other autoimmune diseases such as systemic lupus erythematosis, the correlation between DNA methylation and reactivity of CD4 + T cells was noted early and led to the discovery of several key disease genes (reviewed in [72]). Furthermore, RA synovial fi bro blasts -that is, the eff ector cells of joint and bone destruc tion in RApresent an intrinsic aggressive behaviour even in the absence of cells of the immune system or cytokines. Early work suggested that the DNA of RA synovial fi broblasts is partially hypomethylated, resulting in an activated phenotype [73,74] -an obser vation that more recently could be confi rmed and expanded by showing cytokine regulation of DNA methyl transferase expression, linked to diff erentially methy lated genes, and critical to RA pathogenesis such as CHI3L1, CASP1, STAT3, MAP3K5, MEFV and WISP3 [75,76]. Interestingly, epigenetic inhibitor therapy appears to have therapeutic potential in suppressing proliferation and aggressive phenotype of synovial fi broblasts [77][78][79].
Th e eff ect of inhibition of DNA methyltransferases by 5-aza-deoxycytidine, procainamide or hydralazine on Tcell function, and the subsequent development of systemic lupus erythematosis, underscores the importance of epigenetic modifi cations (in this case, DNA methylation) in autoimmunity [80]. Furthermore, the histone components of nucleosomes and anti-nucleosome antibody-nucleosome adducts have both been implicated as severe immunostimulatory factors [81,82].
As demonstrated by the examples given above, the characterisation of epigenomic modifi cations focusing on post-translational histone modifi cations has started to make signifi cant advances in both the adaptive immune system in T-cell diff erentiation and the innate immune system in, for example, the regulation of TNF gene expression in macrophages.

Interfering with chromatin modifi cations off ers novel possibilities in drug discovery
As discussed above, there are certainly good indicators that epigenetic mechanisms do play a role in pathogenesis and might even be targets for therapeutic intervention (cf. Table 2) within the musculoskeletal disease arena, which includes infl ammatory conditions such as RA as well as degenerative or malignant diseases such as osteoarthritis or bone cancers. Th e target classes identifi ed in these studies comprise well-established HDAC (including clinically used) inhibitors or miRNAs, as well as novel targets such as bromodomains, histone methyltrans ferases or histone demethylases.
Epigenetic target discovery in chronic infl ammatory diseases is expected to mirror the eff orts currently invested in epigenetic drug development in oncology. Th is hypothesis is highlighted by the recent discovery that selective and potent inhibitors can be developed against a class of histone 3 lysine 27 (H3K27) demethylase enzymes, which inhibit proinfl ammatory cytokine production in lipopoly saccharide-stimulated primary macrophages from healthy individuals or RA patients [31]. Th is fi nding led to the discovery that parts of the H3K4 and H3K27 methylation axis, which is regulated by the opposition between Polycomb and Trithorax groups, is inducible by lipopolysaccharide and regulated through NF-κB pathways [29,30]. Th e inhibitor study is the fi rst of its kind, and a proof of concept that modulation of chromatin modifi cation systems is of potential therapeutic benefi t in controlling proinfl ammatory mechanisms. In addition, the lipo poly saccharide response in macrophages was recently discovered to require the H3K4 methyltransferase Kmt2b [83], pointing to novel opportunities to modulate infl am matory responses.
Th e compelling functional impact of epigenomic modulation in the immune system has also recently been demonstrated through the remarkable pharmacology seen with bromodomain and extraterminal bromodomain inhibitor treatment in mouse models of bacterial sepsis [84]. Inhibitors of this bromodomain and extraterminal class have been shown to critically regulate eff ects of MYC and pTEFb transcriptional complexes [84][85][86]. Interestingly, bromodomain and extraterminal bromodomain inhibitor suppresses the expression of a subset of proinfl ammatory cytokines and chemokines such as IL-1β, IL-6, IL-12α, CXCL9 and CCL12 [84]. Although some discrepancies remain with regards to the specifi city of the proinfl ammatory profi les that require further investigation [87], the results clearly support the notion that bromodomain proteins are key regulators of the infl ammatory response and constitute targets for anti-infl ammatory target discovery [87]. Consequently, these data also extend the disease applications of anti-infl ammatory bromodomain inhibitors into metabolic disorders such as obesity and insulin resistance that have a strong infl ammatory component. Regarding other target classes, inhibition of HDACs has been investigated using RNAi in RA demonstrating critical functions of HDAC1 and HDAC2 in synovial fi broblast proliferation and activity [88]. In addition, HDAC inhibitors (for example, MS-275, Trichostatin A) have shown therapeutic activity in inhibition of synovial fi broblast proliferation [77,78] as well as in stress-induced osteoarthritis models -for example, by inhibiting cyclic tensile strain-induced expression of RUNX-2 and ADAMTS-5 via the inhibition of mitogen-activated protein kinase pathway activation in human chondrocytes [89,90].

Conclusion
Th e rise of epigenetics highlights the maturation of an area, created half a century ago, which is still associated with a somewhat blurred defi nition. Despite this uncertainty, epigenetics is now a dynamic discipline, driving new technological advances as well as challenging and revising traditional paradigms of biology. Th rough epigenetics the classic genetic works are now seen in diff erent ways, and com bined they help to understand the roles and interplay of DNA, RNA, proteins, and environment in inheritance and disease aetiology. Th e epigenetics fi eld is anticipated to contribute to understanding of the complexities of genetic regulation, cellular diff erentiation, embryology, aging and disease but also to allow one to systematically explore novel therapeutic avenues, ultimately leading to personalised medicine.
For the foreseeable future, epigenetics will contribute in at least two ways to the understanding of musculoskeletal disease. First, the systematic mapping of functional chromatin elements in combination with GWAS outputs has generated a rich set of hypotheses to be further tested in order to identify relevant pathways, and to understand phenotypic variation and plasticity in human disease. Secondly, epigenetic chemical biology and drug discovery, although in its infancy, has already resulted in identifi cation of novel, possible targets in, for example, infl ammatory disease. Although much has to be learned in terms of mechanisms, therapeutic utility, effi cacy and safety of drugs targeting epigenetic modifi ers in infl ammation, these novel approaches hold promise for the future of drug discovery in infl ammatory and musculoskeletal disease.

Competing interests
The author declares that he has no competing interests.