Epigenetics of Osteoporosis
Authors: Bischof Oliver , Ebert Regina , Taipaleenmäki Hanna , Hesse Eric , Jakob Franz 
Published: September 2021

Fragile bone is the root cause of osteoporosis. For inherited or acquired
reasons, the fragile bone does not provide sufficient fracture resistance to
withstand the physical strains of a normal lifestyle. Accordingly, clinical
characteristics consist of fragility fractures that occur during daily life
activities or low energy trauma. Hip fractures and vertebral fractures are so
called "major osteoporotic fractures”, that also cause the
highest burden of disease. Although the clinical osteoporosis manifestations are
relatively uniform, there is a vast spectrum of underlying molecular causes.
Impaired bone formation, accelerated bone loss, and impaired lifetime adaptive
regeneration according to physical impact characterize the cruder facets of
osteoporosis. The signaling cascades that govern bone formation and metabolism
may be altered by genetically or epigenetically inherited defects or acquired
epigenetic changes due to tissue aging and/or underlying diseases. While
molecular genetics and mechanisms and specific osteoporosis treatments have made
impressive progress over the last three decades, there is still an urgent need
to better understand the role of epigenetics in this disease.

Epigenetic mechanisms such as covalent modifications of DNA, histones, or
essential core factors like the osteogenic transcription factors (e. g.,
RUNX2) and inhibitory modulators of osteogenic WNT-signaling (e. g.,
Dickkopf-1 (DKK-1), sclerostin (SOST)) are all intricately implicated in
developmental bone formation and adaptive regeneration and remodeling processes
throughout adult life. These mechanisms are accompanied by chromatin
architecture and gene expression changes of small (e. g., microRNAs
(miRs)) and long, noncoding RNAs (lncRNAs). The timely execution of these
mechanisms either facilitates or inhibits bone formation and remodeling.
Together, epigenetic mechanisms controlling bone homeostasis widen the spectrum
of potential dysregulations that can cause osteoporosis and open new avenues for
therapeutic interventions.

Apart from the core mechanisms of bone formation and regeneration, recent
research revealed that tissue-resident cells of the immune system such as
tissue-specific macrophages, myeloid precursors, and lymphocytes have
surprisingly fundamental influence on tissue regeneration, including bone. Those
tissue resident cells are also subject to epigenetic changes and may
substantially contribute to the development of disease. Epigenetic
constellations can be inherited, but the dynamic epigenetic mechanisms involved
in physiological processes of tissue regeneration may also be affected by
pathologies such as cellular aging and senescence. Recently, several studies
aimed at identifying DNA methylation signatures in peripheral blood leukocytes
from osteoporosis patients that reveal novel disease mechanisms and potential
targets for diagnosis and treatment. Overall, these studies rendered, however,
yet inconclusive results.

By contrast, studies using bone marrow-derived skeletal progenitors identified
transcriptome changes in osteoporosis patients, which could have epigenetic
reasons in the absence of genetic causes. Respective changes may be related to
the local milieu in bone and bone marrow as a kind of segmental attitude of a
specific tissue acquired through tissue aging and/or supported by
underlying aging-associated diseases such as arteriosclerosis or aging of cells
of the immune system.

In summary, there is cumulating evidence linking epigenetic factors to the
pathogenesis of aging-associated osteoporosis. However, we are currently still
limited in our knowledge with respect to the causal traits that are common,
inherited, or acquired in a lifetime in the respective tissues and cells
involved in bone formation and regeneration. During the following years, the
field will most certainly learn more about molecular processes and factors that
can be targeted therapeutically and/or used as biomarkers for risk
assessment.