Zelluläre Defekte und Regulationsstörungen bei der Heilung osteoporotischer Frakturen

Zusammenfassung

Osteoporose besteht in einer gestörten Adaptation des Knochens an mechanische Anforderungen des Alltags und resultiert im Auftreten von Fragilitätsfrakturen vorwiegend der Wirbelkörper, des Femur, des Radius und des Humerus. Über lange Zeit wurde diskutiert, ob die Frakturheilung bei Osteoporose überhaupt gestört ist, vor allem wegen der Schwierigkeit, geeignete Messparameter für den Ablauf der Frakturheilung zu finden. In den vergangenen Jahren ist auf der Basis präklinischer und klinischer Daten ein Konsensus dahingehend wahrzunehmen, dass bei Osteoporose die Frakturheilung verzögert abläuft und dass nach operativer Versorgung das Implantatversagen gehäuft auftritt. Molekulare Ursachen für diese gestörte Frakturheilung sind bislang nicht in extenso untersucht. Arbeitshypothesen leiten sich aus den modifizierbaren und nicht modifizierbaren Risikofaktoren für die Osteoporose ab und betreffen somit hauptsächlich den Mangel an Sexualhormonen, das Alter, die Immobilisation und die gestörte Mechanotransduktion, sowie den genetischen Hintergrund der Osteoporose. Erste präliminäre Daten aus mesenchymalen Stammzellen im höheren Alter und bei Osteoporose weisen darauf hin, dass die gestörte Regeneration und Knochenheilung eine Folge der verminderten Anzahl an kolonieformenden Stammzellen ist, deren Funktion im Sinne der Migration und Rekrutierung gestört ist, deren Mechanosensitivität vermindert ist und die frühzeitig autoinhibitorische Proteine exprimieren und in die Seneszenz eintreten. Viele Hinweise konzentrieren sich auf den wnt/frz- Signalweg und dessen Hemmproteine wie “secreted frizzled related proteins” SFRP und Sclerostin. Die Erforschung der Frakturheilung in monogenetischen Osteoporosemodellen und in menschlichen Zellen mit Regenerationspotential wird sicher spezifische Defekte aufdecken, die es erlauben, gezielte Interventionsstudien zur Verbesserung der Frakturheilung bei Osteoporose präklinisch und klinisch durchzuführen.

Summary

Osteoporosis is a syndrome of altered bone adaptation to mechanical strain in every-daylife resulting in fragility fractures of mainly vertebrae, the femur, radius and humerus. For many years the scientific community discussed if at all fracture healing is altered in osteoporosis and this was mainly due to the fact that it was difficult to find suitable readouts to evaluate the time course and quality of fracture healing in pathology. In recent years consensus has been achieved in that fracture healing in osteoporosis is delayed and implant failure after surgical stabilization is comparably common. The molecular causes for this alteration have so far not been unraveled in detail. Working hypotheses have been concluded from modifiable and non-modifiable clinical risk factors, e. g. sex hormone deficiency, advanced age, immobilization and altered mechanotransduction and from the genetic background of osteoporosis. Preliminary data obtained from mesenchymal stem cells in aged organisms and in osteoporosis suggest that altered bone regeneration and fracture healing in osteoporosis is a consequence of the diminished number of colony forming stem cells, the function of which is impaired in terms of migration and recruitment, mechanosensitivity, and which are prone to premature expression of autoinhibitory proteins and to replicative senescence. Several sets of data are focusing on the wnt/ frz signaling pathway and its inhibitors like “secreted frizzled related proteins” (SFRP) and sclerostin (SOST). Research in fracture healing in monogenetic mouse models of osteoporosis and in human cells involved in bone regeneration and fracture healing will unravel specific defects and alterations of regulation, which will allow targeted intervention to enhance osteoporotic fracture healing in preclinical models and clinical studies.

Schlüsselwörter

Osteoporose - Mechanotransduktion - Altern - gestörte Frakturheilung - wnt/frz-Signalweg - “secreted frizzled related proteins” SFRP - Sclerostin

Keywords

Osteoporosis - mechanotransduction - aging - fracture healing - wnt/frz signaling pathway - “secreted frizzled related proteins” (SFRP) - sclerostin

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