Epigenetics refers to the study of mechanisms able to influence gene expression in a stable and potentially heritable manner without altering the DNA sequence. These mechanisms include posttranslational histone modifications, miRNA-mediated post-transcriptional regulation and DNA methylation. The accumulation of molecular errors over time resulting, at least partly, in the alteration of normal epigenetic patterns is being widely associated with aging. Epigenetic processes are also considered important mechanisms through which environmental and stochastic stressors promote numerous pathologies in humans. It is, therefore, reasonable to expect that several complex multi-factorial late-onset disorders, like osteoporosis and osteoarthritis, could have a strong epigenetic component. The focal point of all skeletal pathologies is the deregulation of bone remodeling, mediated by bone-forming osteoblasts and bone-resorbing osteoclasts. In order to keep both processes in balance, the activity, differentiation and apoptosis of both cell types have to be tightly regulated. In particular, the differentiation of osteoblasts and osteoclasts is accompanied by profound changes in gene expression. It has been shown that histone deacetylation and DNA methylation negatively regulate the expression of several genes associated with different stages of osteoblast differentiation; however, several miRNAs promote osteoblastogenesis. Furthermore, inactivating mutations in the miRNA coding regions could be associated with the pathogenesis of osteoporosis. The aim of this review is to highlight the role of epigenetic mechanisms in bone remodeling and bone homeostasis, so as to implicate their diagnostic and therapeutic potential in skeletal diseases.

Epigenetic mechanisms including posttranslational histone modifications and DNA methylation are emerging as important determinants of bone homeostasis. With our case-control study we aimed to identify which chromatin-modifying enzymes could be involved in the pathology of postmenopausal osteoporosis and osteoarthritis while co-regulated by estrogens, oxidative stress and hypoxia. Gene expression of HAT1, KAT5, HDAC6, MBD1 and DNMT3A affected by oxidative stress and hypoxia in an in vitro qPCR screening step performed on an osteoblast cell line was analysed in trabecular bone tissue samples from 96 patients. Their expression was significantly reduced in patients with postmenopausal osteoporosis and osteoarthritis as compared to autopsy controls and significantly correlated with bone mineral density and several bone histomorphometry-derived parameters of bone quality and quantity as well as indicators of oxidative stress, RANK/RANKL/OPG system and angiogenesis. Furthermore, oxidative stress increased DNA methylation levels at the RANKL and OPG promoters while decreasing histone acetylation levels at these two genes. Our study is the first to show that higher expression of HAT1, HDAC6 and MBD1 is associated with superior quantity as well as quality of the bone tissue having a more favourable trabecular structure.

Ustekinumab is a monoclonal antibody used in Crohn’s disease (CD). Dose optimization in case of non-response and the role of pharmacokinetic–pharmacodynamic (PK-PD) monitoring remain unresolved dilemmas in clinical practice. We aimed to develop a population PK-PD model for ustekinumab in CD and simulate efficacy of alternative dosing regimens. We included 57 patients and recorded their characteristics during 32 weeks after starting with ustekinumab therapy. Serum ustekinumab concentration was prospectively measured and fecal calprotectin (FC) concentration was used to monitor the disease activity. Ustekinumab PK-PD was described by a two-compartment target-mediated drug disposition model linked to an indirect response model. Lower fat-free mass, higher serum albumin, previous non-exposure to biologics, FCGR3A-158 V/V variant and lower C-reactive protein were associated with higher ustekinumab exposure. Model-based simulation suggested that 41.9% of patients receiving standard dosing achieve biochemical remission at week 32. In patients not achieving remission with standard dosing at week 16, transition to 4-weekly subcutaneous maintenance dosing with or without intravenous reinduction resulted in comparably higher remission rates at week 32 (51.1% vs. 49.2%, respectively). Our findings could be used to guide stratified ustekinumab treatment in CD, particularly in patients with unfavorable characteristics, who might benefit from early transition to 4-weekly maintenance dosing.