The role of TGF-β isoforms and osteoprogenitor cells in the pathogenesis of heterotopic ossification : an experimental and clinical study of hip arthroplasty

Abstract

Dissertation focuses on the changes in the content and expression of transforming growth factor beta isoforms (TGF-β1, TGF-β2 and TGF-β3) in heterotopic ossification (HO) during its formation. Since the HOs formed after total hip arthroplasty (THA) are clinically frequent (with approximately 37% of THA patients being affected), material was collected from patients who had undergone the above mentioned operation and came for revision surgery and material was also collected from an animal model mimicking the situation after THA in order to study initial and early changes of HO formation (days 3 and 21). TGF-β isoforms were chosen as these growth factors have many functions in the body and in the bone, but they have hardly been studied in the context of HO formation. Also the changes in the morphology of HO were followed during its formation. The main findings of this study were the specific changes in the content and expression of the less spread isoforms TGF-β2 and TGF-β3. However, this kind of dynamics was not found for the more spread isoform TGF-β1 (content in normal bone tissue about 200 µg/kg). The similar features in the dynamics of TGF-β isoforms in humans and in the animal model suggest that this model can be used to evaluate the dynamics of these growth factors and initial and early stages of HO formation. In addition it was found that by allowing the access of the cells from the open femoral canal to the site of HO formation in our animal model the HO formation was not significantly affected, which suggest that local biochemical signals play the most important role.Dissertatsioon keskendub muutustele transformeeriva kasvufaktori beeta isovormide (TGF-β1,TGF-β2 ja TGF-β3) sisalduses ja ekspressioonis skeletivälises luus e heterotoopses ossifikatsioonis (HO) selle moodustumise käigus. Kuna kliiniliselt on kõige levinumaks HO-d, mis on tekkinud pärast puusaliigese endoproteesimist (esineb ligikaudu 37% patsientidest), koguti materjali nii patsientidelt, kes olid nimetatud operatsiooni läbinud ja tulid kordusoperatsioonile kui ka loommudelist, milles rottidel jäljendati puusaliigese endoproteesimisel tekkivat olukorda, et uurida HO tekke varajasi etappe (3 ja 21 päeva). TGF-β isovormidele keskenduti kui organismis ja luukoes erinevaid funktsioone täitvatele, kuid HO tekke kontekstis vähe uuritud kasvufaktoritele. Samuti jälgiti muutusi HO morfoloogias selle kasvamise ajal. Uurimustöö olulisemateks leidudeks olid spetsiifilised muutused vähemlevinud TGF-β isovormide (TGF-β2 ja TGF-β3) sisalduses ja ekspressioonis, kuna luukoes enimlevinud isovormi TGF-β1 puhul (sisaldus luukoes 200 µg/kg) sellist dünaamikat ei täheldatud. Sarnased jooned TGF-β isovormide dünaamikas nii inimestel kui loommudelis viitavad sellele, et antud mudel sobib nimetatud kasvufaktorite ja HO tekke varajaste etappide uurimiseks. Lisaks ilmnes, et luuüdikanali rakkude juurdepääsu lubamine HO tekkekohale luuüdikanali avamise teel, ei mõjutanud loommudelis HO teket olulisel määral, millest võib järeldada, et siin on suurem roll lokaalsetel biokeemilistel signaalidel.