Cindy Boer

38 | Chapter 1.2 Whether related to parental influences or not, a few studies reported an associ- ation of the methylation of some genes (such as NOS, RXRA , and CDKN2A ) in cord blood and childhood bone mass[20-22]. However, those results have not been confirmed in other cohorts yet. Although less studied than the relationship between early life expe- riences and osteoporosis, some data support a developmental component in OA. For example, exposure to Chinese famine during childhood has been associated with arthri- tis (including both OA and inflammatory arthritis) in later life[23]. Similarly, in a Brit- ish study, lower weight at birth and year 1 was associated with higher rates of OA[24]. Weight and body length differences, which have a clear developmental component, may explain, at least in part, those associations. Another example is finger length pat- tern, which is thought to be an indicator of prenatal androgen exposure. Type 3 finger length pattern (longer fourth digit than second digit) has been associated with having symptomatic knee OA and chronic pain[25]. which might be explained by an influence of embryogenic sex hormone exposure on brain development[26]. It is thought that epigenetic programming plays a role in all of these associations, but the exact role of epigenetic factors in the relation between prenatal exposures and skeletal diseases has not been elucidated yet. Epigenomic plasticity in adult life In addition to the developmental epigenetic programming, there is an enormous epig- enomic plasticity in adult life. The variance in epigenetic marks increases with age, which is thought to reflect the response to environmental exposures in such a way that they modulate the expression of genes. However, studies in highly inbred rodent lines highlighted that a part of the phenotypic variation could not be attributed to environ- mental exposures[27]. Also, monozygotic twin studies examining discordances have shown that part of the phenotypic variation is attributed to so‐called “stochastic” vari- ation, possibly caused by “molecular noise” due to imperfect control of the molecular interactions in the cell[28]. Stochasticity, or random variation, is thought to have a large impact on disease susceptibility[29, 30]. DNA Methylation and Skeletal Disorders DNA methylation and the differentiation of skeletal cells Osteoclast precursors derive from hematopoietic stem cells, whereas the bone‐ and cartilage‐forming cells, osteoblasts and chondrocytes, derive from mesenchymal stem