Epigenetics of Osteoporosis

Abstract

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.

Zusammenfassung

Man spricht von Osteoporose, wenn der Knochen von der Entwicklung her so fragil angelegt ist oder im Lauf des Lebens sich dahingehend verändert hat, dass er nicht die ausreichende Bruchfestigkeit aufweist, um den physikalischen Belastungen eines durchschnittlichen Lebens standzuhalten. Knochenbrüche bei inadäquater Belastung oder Niedrig-Energie-Trauma, Fragilitätsfrakturen, sind demgemäß die klinischen Charakteristika. Die häufigsten Frakturen, gleichzeitig diejenigen mit den schwerwiegendsten klinischen Auswirkungen, sind hüftnahe Frakturen des Femur und vertebrale Frakturen. Auch wenn die klinischen Manifestationen der Osteoporose relativ uniform erscheinen, gibt es eine sehr breite Palette möglicher molekularer Ursachen. Beeinträchtigter Knochenaufbau, beschleunigter Knochenabbau und Beeinträchtigung der lebenslangen Adaptation und Regeneration stellen die groben Facetten der Erkrankung dar. Osteogene Signalkaskaden können genetisch, epigenetisch oder durch andere Krankheiten Regulationsstörungen aufweisen, die den Knochenmetabolismus sekundär verändern. Zwar hat sich die Forschung über die molekularen Mechanismen und die Entwicklung zielgenauer Medikamente in den letzten Dekaden sehr rasch entwickelt, am wenigsten aber ist derzeit über die spezifischen epigenetischen Ursachen bekannt. Epigenetische Mechanismen wie Methylierung von DNA und Histonen, Acetylierung von Histonen und Expression verschiedener nichtkodierender RNA-Moleküle (ncRNA) sind sehr eng verknüpft mit der Knochenformation während der Entwicklung und der Regeneration, aber auch mit dem adaptiven Remodeling im Erwachsenenalter. Essentielle Regulatoren der Knochenformation wie der osteogene Transkriptionsfaktor RUNX2 und die Inhibitoren osteogener wnt-Signalkaskaden Dickkopf-1 (DKK1) und Sklerostin (SOST) werden wie auch viele nachgeordnete osteogene Proteine physiologischerweise im Rahmen der Differenzierungsprogramme skelettaler Vorläuferzellen durch Methylierung von DNA und andere epigenetische Mechanismen moduliert. Hand in Hand damit finden Veränderungen der Chromatin-Architektur statt, die z. B. durch polycomb-Proteinkomplexe wie PRC2 und durch (De-) Methylierung und (De-)Acetylierung von Histonen sowie durch Expression bestimmter nicht-kodierender RNAs gemeinsam orchestriert werden, und Knochen-Formation oder -Abbau begünstigen oder verhindern. Von daher wissen wir, dass physiologischerweise Knochenentwicklung und Remodellierung im Erwachsenenalter mit epigenetischen Regulationsmechanismen gesteuert werden kann. Dies öffnet folgerichtig auch alle Türen für die Entwicklung von Fehlregulationen und Pathologien, die Krankheiten begünstigen, auch die Entstehung der Osteoporose. Über die zentral an der Knochenformation beteiligten Zelltypen hinaus hat jüngste Forschung Erkenntnisse darüber erbracht, wie überraschend essenziell der Einfluss gewebe-spezifischer residenter Zellen des Immunsystems auf die Geweberegeneration ist, beispielsweise gewebespezifischer Makrophagen und myeloischer Vorläufer oder Lymphozyten. Solche innovativen Aspekte der Geweberegeneration im Allgemeinen eröffnen ein neues Level der Komplexität, besonders was die epigenetischen Mechanismen der intrinsischen Gewebe-Regeneration anbelangt. Im Besonderen eröffnen sie neue Fragen über mögliche epigenetische Ursachen defizienter Regeneration oder eintretender Degeneration in Geweben nicht nur in den gewebeeigenen Zellen, in diesem Fall Osteoblasten / Osteozyten und Osteoklasten, sondern auch in spezifischen Kompartimenten wie beispielsweise den gewebe-residenten Zellen des Immunsystems. Prinzipiell sind epigenetische Konstellationen erblich, es gibt aber auch die erwähnten, sich dynamisch verändernden Aktivitäten epigenetischer Regulations-Mechanismen, die ihrerseits wiederum im Rahmen von Pathologie-Entwicklung zur Krankheitsursache werden können. In den letzten Jahren wurden Untersuchungen durchgeführt, die in der DNA peripherer Leukozyten und in skelettalen Vorläuferzellen aus dem Knochenmark bei OsteoporosepatientInnen im Vergleich zu knochengesunden Personen nach epigenetischen Veränderungen gesucht haben, die ursächlich für die Osteoporose sein könnten. Ziele solcher Untersuchungen sind neben dem besseren Verständnis der Pathogenese der Erkrankung die Identifizierung neuer therapeutischer Zielmoleküle und / oder die Etablierung epigenetischer Marker als Risikoindikatoren. Einige Arbeiten konnten differentielle Methylierungsmuster in bestimmten Genregionen in der DNA zirkulierender Blutzellen finden, sowohl in solchen Genen die zentral mit dem Knochenstoffwechsel verknüpft sind als auch in solchen die man bisher nicht mit der Knochenbiologie in Verbindung brachte. Andere Arbeiten fanden in der DNA der mononukleären Blutzellen bei Berechnung mit hoher Stringenz keine signifikanten Veränderungen. Mehrere Arbeiten jedoch erbrachten Hinweise darauf, dass EZH2, ein Mitglied des polycomb Komplexes PRC2 mit Methyltransferase-Aktivität, signifikant bei Osteoporose überexprimiert wird und überaktiv ist. Solche Mechanismen dürfen als Kandidaten für epigenetische Ursachen der Osteoporose angesehen werden, die Ergebnisse sind aber derzeit noch nicht konsistent. Es gab bei OsteoporosepatientInnen keine Hinweise für eine Progerie-Konstellation, eine frühzeitige Alterung mit systemischen Auswirkungen. Untersuchungen an skelettalen Vorläuferzellen im Knochenmark, ergaben jedoch eindeutige Veränderungen des Transkriptoms skelettaler Vorläuferzellen bei OsteoporosepatientInnen, was bei Fehlen relevanter genetischer Veränderungen am ehesten im Sinne epigenetischer Ursachen zu interpretieren ist. Diese sind möglicherweise beschränkt auf das Milieu im Knochen und Knochenmark und daher peripher nicht eindeutig zu identifizieren. Am ehesten sind diese Veränderungen epigenetischer Regulation als segmentale Störung im Lauf des Lebens akquiriert, die durch Gewebealterung und begünstigende Krankheiten anderer Gewebe ein Regenerationsdefizit bedingen. Zusammengefasst ergeben sich eindeutige Hinweise dafür, dass die altersassoziierte Osteoporose epigenetische Ursachen hat. Wir wissen aber noch nicht, welche charakteristischen epigenetisch veränderten übergeordneten Schaltstellen es gibt, die über Generationen vererbt werden und / oder im Lauf des Lebens im Gewebe erworben werden. In den nächsten Jahren ist mit Sicherheit zu erwarten, dass neue Zielmechanismen für die Therapie entdeckt werden und Risikokonstellationen mit epigenetischen Markern beschrieben werden können.

Key words

Epigenetics - noncoding RNAs - Bone biology - osteoporosis - bone remodeling

Schlüsselwörter

Epigenetik - nichtkodierende RNAs - Knochenbiologie - Osteoporose - Knochen-Remodeling

Publikationsverlauf

Eingereicht: 08. Juni 2021

Angenommen: 11. Juni 2021

Artikel online veröffentlicht:
17. September 2021

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