Complementary and synergistic effects on osteogenic and angiogenic properties of copper-incorporated silicocarnotite bioceramic: In vitro and in vivo studies.

Promoting bone regeneration to treat bone defects is a challenging problem in orthopedics, and developing novel biomaterials with both osteogenic and angiogenic activities is sought as a feasible solution. Here, copper-silicocarnotite [Cu-Ca5(PO4)2SiO4, Cu-CPS] was designed and fabricated. In this study, the Cu-CPS ceramics demonstrated better mechanical, osteogenic, and angiogenic properties in vitro and in vivo than pure CPS one. Particularly, CPS with 1.0 wt% CuO (1.0Cu-CPS) exhibited the best performance. Additionally, hydroxyapatite with 1.0 wt% CuO (1.0Cu-HA) was used to explore the respective effects of copper and silicon (Si). According to the in vitro results, it indicated that Cu enhanced the osteogenic activity of CPS ceramics although Si played a dominate role in the osteogenic process. Moreover, Cu could promote an early stage of angiogenesis, and the complementary effect of Si and Cu was found in the late phase. Furthermore, the in vivo results illustrated that the synergistic effect of Cu and Si improved bone and vessel regeneration during the degradation of Cu-CPS scaffolds (P < 0.05). Therefore, Cu-CPS ceramics could improve osteogenesis and angiogenesis through the simultaneous effects of Cu and Si, thus, offering a promising treatment option in orthopedic application for bone tissue regeneration.

High-Dose TGF-ß1 Impairs Mesenchymal Stem Cell-Mediated Bone Regeneration via Bmp2 Inhibition.

Transforming growth factor-ß1 (TGF-ß1) is a key factor in bone reconstruction. However, its pathophysiological role in non-union and bone repair remains unclear. Here we demonstrated that TGF-ß1 was highly expressed in both C57BL/6 mice where new bone formation was impaired after autologous bone marrow mesenchymal stem cell (BMMSC) implantation in non-union patients. High doses of TGF-ß1 inhibited BMMSC osteogenesis and attenuated bone regeneration in vivo. Furthermore, different TGF-ß1 levels exhibited opposite effects on osteogenic differentiation and bone healing. Mechanistically, low TGF-ß1 doses activated smad3, promoted their binding to bone morphogenetic protein 2 (Bmp2) promoter, and upregulated Bmp2 expression in BMMSCs. By contrast, Bmp2 transcription was inhibited by changing smad3 binding sites on its promoter at high TGF-ß1 levels. In addition, high TGF-ß1 doses increased tomoregulin-1 (Tmeff1) levels, resulting in the repression of Bmp2 and bone formation in mice. Treatment with the TGF-ß1 inhibitor SB431542 significantly rescued BMMSC osteogenesis and accelerated bone regeneration. Our study suggests that high-dose TGF-ß1 dampens BMMSC-mediated bone regeneration by activating canonical TGF-ß/smad3 signaling and inhibiting Bmp2 via direct and indirect mechanisms. These data collectively show a previously unrecognized mechanism of TGF-ß1 in bone repair, and TGF-ß1 is an effective therapeutic target for treating bone regeneration disability. © 2019 American Society for Bone and Mineral Research.