Vukicevic Slobodan, Oppermann Hermann, Verbanac Donatella, Jankolija Morana, Popek Irena, Curak Jasna, Brkljacic Jelena, Pauk Martina, Erjavec Igor, Francetic Igor, Dumic-Cule Ivo, Jelic Mislav, Durdevic Dragan, Vlahovic Tomislav, Novak Ruder, Kufner Vera, Bordukalo Niksic Tatjana, Kozlovic Marija, Banic Tomisic Zrinka, Bubic-Spoljar Jadranka, Bastalic Ivancica, Vikic-Topic Smiljka, Peric Mihaela, Pecina Marko, Grgurevic Lovorka
Laboratory for Mineralized Tissues, Center for Translational and Clinical Research, University of Zagreb School of Medicine, Salata 11, 10000, Zagreb, Croatia,
Int Orthop. 2014 Mar;38(3):635-47. doi: 10.1007/s00264-013-2201-1. Epub 2013 Dec 19.
The purpose of this study was to revise the clinical use of commercial BMP2 (Infuse) and BMP7 (Osigraft) based bone devices and explore the mechanism of action and efficacy of low BMP6 doses in a novel whole blood biocompatible device OSTEOGROW.
Complications from the clinical use of BMP2 and BMP7 have been systemically reviewed in light of their role in bone remodeling. BMP6 function has been assessed in Bmp6-/- mice by μCT and skeletal histology, and has also been examined in mesenchymal stem cells (MSC), hematopoietic stem cells (HSC) and osteoclasts. Safety and efficacy of OSTEOGROW have been assessed in rats and rabbits.
Clinical use issues of BMP2 and BMP7 have been ascribed to the limited understanding of their role in bone remodeling at the time of device development for clinical trials. BMP2 and BMP7 in bone devices significantly promote bone resorption leading to osteolysis at the endosteal surfaces, while in parallel stimulating exuberant bone formation in surrounding tissues. Unbound BMP2 and BMP7 in bone devices precipitate on the bovine collagen and cause inflammation and swelling. OSTEOGROW required small amounts of BMP6, applied in a biocompatible blood coagulum carrier, for stimulating differentiation of MSCs and accelerated healing of critical size bone defects in animals, without bone resorption and inflammation. BMP6 decreased the number of osteoclasts derived from HSC, while BMP2 and BMP7 increased their number.
Current issues and challenges with commercial bone devices may be resolved by using novel BMP6 biocompatible device OSTEOGROW, which will be clinically tested in metaphyseal bone fractures, compartments where BMP2 and BMP7 have not been effective.
本研究旨在修订基于商业骨形态发生蛋白2（Infuse）和骨形态发生蛋白7（Osigraft）的骨装置的临床应用，并探索低剂量骨形态发生蛋白6在新型全血生物相容性装置OSTEOGROW中的作用机制和疗效。
根据骨形态发生蛋白2和骨形态发生蛋白7在骨重塑中的作用，系统回顾了其临床应用并发症。通过显微计算机断层扫描（μCT）和骨骼组织学评估了骨形态发生蛋白6在Bmp6基因敲除小鼠中的功能，并在间充质干细胞（MSC）、造血干细胞（HSC）和破骨细胞中进行了检测。在大鼠和兔子中评估了OSTEOGROW的安全性和疗效。
骨形态发生蛋白2和骨形态发生蛋白7的临床应用问题归因于在临床试验装置开发时对其在骨重塑中作用的理解有限。骨装置中的骨形态发生蛋白2和骨形态发生蛋白7显著促进骨吸收，导致骨内膜表面骨溶解，同时刺激周围组织过度骨形成。骨装置中未结合的骨形态发生蛋白2和骨形态发生蛋白7沉淀在牛胶原蛋白上，引起炎症和肿胀。OSTEOGROW在生物相容性血凝块载体中应用少量骨形态发生蛋白6，可刺激间充质干细胞分化，加速动物临界尺寸骨缺损的愈合，且无骨吸收和炎症。骨形态发生蛋白6减少了造血干细胞来源的破骨细胞数量，而骨形态发生蛋白2和骨形态发生蛋白7增加了其数量。
使用新型骨形态发生蛋白6生物相容性装置OSTEOGROW可能解决商业骨装置当前的问题和挑战，该装置将在干骺端骨折中进行临床试验，而在这些部位骨形态发生蛋白2和骨形态发生蛋白7尚未有效。
