Current Genomics - Volume 16, Issue 6, 2015

Human Mesenchymal Stem Cells (hMSCs) have emerged in the last few years as one of the most promising therapeutic cell sources and, in particular, as an important tool for regenerative medicine of skeletal tissues. Although they present a more restricted potency than Embryonic Stem (ES) cells, the use of hMCS in regenerative medicine avoids many of the drawbacks characteristic of ES cells or induced pluripotent stem cells. The challenge in using these cells lies into developing precise protocols for directing cellular differentiation to generate a specific cell lineage. In order to achieve this goal, it is of the upmost importance to be able to control de process of fate decision and lineage commitment. This process requires the coordinate regulation of different molecular layers at transcriptional, posttranscriptional and translational levels. At the transcriptional level, switching on and off different sets of genes is achieved not only through transcriptional regulators, but also through their interplay with epigenetic modifiers. It is now well known that epigenetic changes take place in an orderly way through development and are critical in the determination of lineagespecific differentiation. More importantly, alteration of these epigenetic changes would, in many cases, lead to disease generation and even tumour formation. Therefore, it is crucial to elucidate how epigenetic factors, through their interplay with transcriptional regulators, control lineage commitment in hMSCs.

DNA methylation in eukaryotes invokes heritable alterations of the of the cytosine base in DNA without changing the underlying genomic DNA sequence. DNA methylationmay be modified by environmental exposures as well as gene polymorphisms and may be a mechanistic link between environmental risk factors and the development of disease. In this review, we consider the role of DNA methylation in bone cells (osteoclasts/osteoblasts/osteocytes) and their progenitorswith special focus on in vitro and ex vivo analyses. The number of studies on DNA methylation in bone cells is still somewhat limited, nevertheless it is getting increasingly clear that this type of the epigenetic changes is a critical regulator of gene expression. DNA methylation is necessary for proper development and function of bone cells and is accompanied by disease characteristic functional alterations as presently reviewed including postmenopausal osteoporosis and mechanical strain.

Osteoarthritis (OA) is an age-related disease with poorly understood pathogenesis. Recent studies have demonstrated that miRNA might play a key role in OA initiation and development. We reviewed recent publications and elucidated the connection between miRNA and OA cartilage anabolic and catabolic signals, including four signaling pathways: TGF-β/Smads and BMPs signaling, associated with cartilage anabolism; and MAPK and NF-KB signaling, associated with cartilage catabolism. We also explored the relationships with MMP, ADAMTS and NOS (NitricOxide Synthases) families, as well as with the catabolic cytokines IL-1 and TNF-α. The potential role of miRNAs in biological processes such as cartilage degeneration, chondrocyte proliferation, and differentiation is discussed. Collective evidence indicates that miRNAs play a critical role in cartilage degeneration. These findings will aid in understanding the molecular network that governs articular cartilage homeostasis and in to elucidate the role of miRNA in the pathogenesis of OA.

Osteoporosis is a systemic disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and propensity to fracture. Environmental factors during early life, including those in utero, may influence bone mass during later life and, consequently, the risk of osteoporosis. Epigenetic mechanisms play central roles in the differentiation of bone cells, osteoblasts and osteoclasts, responsible for bone formation and bone resorption, respectively. A few studies have shown some differentially methylated genes in patients with osteoporosis. They include genes belonging to the Wnt pathway, which is an important regulator of osteoblast differentiation, and other genes involved in the development of the skeleton. Likewise, some miRNAs may be differentially expressed in these patients. However, those preliminary results need to be replicated in other cohorts. Unlike the genome, the epigenome is cell-specific and changes with aging and environmental factors. Therefore, the design and interpretation of epigenetic epidemiology studies pose a number of practical difficulties. A framework for the critical appraisal of these studies is proposed.

Osteoporosis is one of the most prevalent skeletal disorders and has enormous public health consequences due to the morbidity and mortality of the resulting fractures. This article discusses the developmental origins of osteoporosis and outlines some of the modifiable and non-modifiable risk factors in both intrauterine and postnatal life that contribute to the later onset of osteoporosis. Evidence for the effects of birth size and early growth in both preterm and term born infants are discussed and the role of epigenetics within the programming hypothesis is highlighted. This review provides compelling evidence for the developmental origins of osteoporosis and highlights the importance of osteoporosis prevention at all stages of the life course.

Osteoarthritis (OA) is a prevalent disease of articular joints and primarily characterized by degradation and calcification of articular cartilage. Presently, no effective treatment other than pain relief exists and patients ultimately need to undergo replacement surgery of the affected joint. During disease progression articular chondrocytes, the single cell type present in articular cartilage, show altered transcriptional profiles and undergo phenotypic changes that resemble the terminal differentiation route apparent in growth plate chondrocytes. Hence, given its prominent function in both regulating gene expression and maintaining cellular phenotypes, DNA methylation of CpG dinucleotides is intensively studied in the context of OA. An increasing number of studies have been published that employed a targeted approach on genes known to play a role in OA pathophysiology. As of such, it has become clear that OA responsive DNA methylation changes seem to mediate disease associated aberrant gene expression. Furthermore, established OA susceptibility alleles such as GDF5 and DIO2 appear to confer OA risk via DNA methylation and respective pathophysiological expression changes. In more recent years, genome wide profiling of DNA methylation in OA affected articular cartilage has emerged as a powerful tool to address the epigenetic changes in their entirety, which has resulted in the identification of putative patient subgroups as well as generic OA associated pathways.

Skeletal development is a multistage process during which mesenchymal progenitor cells undergo proliferation and differentiation and subsequently give rise to bone and cartilage forming cells. Each step is regulated by various transcription factors and signaling molecules. microRNAs are small non-coding RNAs that post-transcriptionally regulate gene expression. Several in vivo and in vitro studies have shown that miRNAs play significant roles in skeletal development. Identifying their functions may give insights into the treatment of developmental disorders of the skeleton. This review summarizes miRNAs that have been shown to participate in various stages of skeletal development by targeting crucial factors.

The best-known phenomenon exemplifying epigenetic drift (the alteration of epigenetic patterns during aging) is the gradual decrease of global DNA methylation. Aging cells, different tissue types, as well as a variety of human diseases possess their own distinct DNA methylation profiles, although the functional impact of these is not always clear. DNA methylation appears to be a dynamic tool of transcriptional regulation, with an extra layer of complexity due to the recent discovery of the conversion of 5-methylcytosine into 5-hydroxymethylcytosine. This age-related DNA demethylation is associated with changes in histone modification patterns and, furthermore, we now know that ncRNAs have evolved in eukaryotes as epigenetic regulators of gene expression. In this review, we will discuss current knowledge on how all these epigenetic phenomena are implicated in human aging, and their links with external, internal and stochastic factors which can affect human age-related diseases onset.

Bone has multiple functions, both morphologically and physiologically, and it frequently features in the pathological condition, including fracture and osteoporosis. For bone regeneration therapy, the regulation of osteoblast differentiation is important. MicroRNA (miRNA)s are short noncoding RNA which regulate gene expression at the post-transcriptional level. MiRNAs play an important role not only in a variety of other cellular processes including differentiation, proliferation, and apoptosis but also in the pathogenesis of human diseases. Recently, miRNAs have been known to participate in osteoblast differentiation by regulating several signaling pathways including transcription factors. New insight into the mechanism during osteogenes is affected by miRNAs has been gained. Moreover, therapeutic trials for bone diseases including osteoporosis, fracture and bone defects targeting miRNAs have been examined in animal models. MiRNA therapy will enable development of a bone regeneration therapy.