scholarly journals Inhibition of Microtubule Assembly in Osteoblasts Stimulates Bone Morphogenetic Protein 2 Expression and Bone Formation through Transcription Factor Gli2

2008 ◽  
Vol 29 (5) ◽  
pp. 1291-1305 ◽  
Author(s):  
Ming Zhao ◽  
Seon-Yle Ko ◽  
Jin-Hua Liu ◽  
Di Chen ◽  
Jianghong Zhang ◽  
...  
Keyword(s):  
Bone Formation ◽  
Bone Morphogenetic Protein ◽  
Molecular Mechanisms ◽  
Fracture Repair ◽  
Microtubule Assembly ◽  
Bone Morphogenetic Protein 2 ◽  
Microtubule Inhibitors ◽  
Morphogenetic Protein ◽  
Hh Signaling

ABSTRACT Bone morphogenetic protein 2 (BMP-2) is essential for postnatal bone formation and fracture repair. By screening chemical libraries for BMP-2 mimics using a cell-based assay, we identified inhibitors of microtubule assembly as stimulators of BMP-2 transcription. These microtubule inhibitors increased osteoblast differentiation in vitro, stimulated periosteal bone formation when injected locally over murine calvaria, and enhanced trabecular bone formation when administered systemically in vivo. To explore molecular mechanisms mediating these responses, we examined effects of microtubule inhibitors on the hedgehog (Hh) pathway, since this pathway is known to regulate BMP-2 transcription in osteoblasts and microtubules have been shown to be involved in Hh signaling in Drosophila. Here we show that in osteoblasts, inhibition of microtubule assembly increased cytoplasmic levels and transcriptional activity of Gli2, a transcriptional mediator of Hh signaling that we have previously shown to enhance BMP-2 expression in osteoblasts (M. Zhao et al., Mol. Cell. Biol. 26:6197-6208, 2006). Microtubule inhibition blocked β-TrCP-mediated proteasomal processing of Gli2 in osteoblasts. In summary, inhibition of microtubule assembly enhances BMP-2 gene transcription and subsequent bone formation, in part, through inhibiting proteasomal processing of Gli2 and increasing intracellular Gli2 concentrations.

scholarly journals Biodegradable Antimicrobial Agent/Analgesic/Bone Morphogenetic Protein-Loaded Nanofibrous Fixators for Bone Fracture Repair

2021 ◽  
Author(s):  
Yi-Hsun Yu ◽  
Yu-Ting Lin ◽  
Yung-Heng Hsu ◽  
Ying-Chao Chou ◽  
Wen-Neng W. N. Ueng ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Bone Fracture ◽  
Antimicrobial Agents ◽  
Cartilage Damage ◽  
Fracture Repair ◽  
Bone Morphogenetic Protein 2 ◽  
Burst Release ◽  
Morphogenetic Protein

Abstract Background Post-operative infection and pain management are two critical aspects that are of great concern to orthopedic surgeons. Although there are several protocols available to deal with these issues, they are fraught with complications such as cartilage damage, cardiovascular and neurological intoxication, and systemic adverse responses. Therefore, it is necessary to develop safe and effective perioperative protocols. In the present study, antimicrobial agents/analgesics/growth factor-embedded biodegradable hybrid fixators (polycaprolactone fixator + poly[lactide-co-glycolide] sheath-core structured nanofibers) for bone fracture repair were designed. These fixators were fabricated using solution-extrusion three-dimensional printing and electrospinning. The in vitro and in vivo release of the incorporated vancomycin, ceftazidime, lidocaine, and bone morphogenetic protein-2 (BMP-2) was evaluated. The in vivo efficacy of the biomolecule-loaded nanofibrous fixators was investigated in rabbit rib-fracture models. Results The nanofibrous fixators were shown to release vancomycin, ceftazidime, and lidocaine in a sustained manner in both in vitro and in vivo conditions and protected BMP-2 from burst release. The implantation of these hybrid fixators around the fractured rib significantly improved animal activities and bone union indicating that the inclusion of analgesic in the fixator effectively reduced the post-surgical pain and thereby helped in recovery. Conclusions The novel biomolecule-loaded nanofibrous hybrid fixators resulted in excellent therapeutic outcomes. They may be effective in the repair of rib fractures in clinical settings and may help deal with surgical complications such as infection, non-union, and intolerable post-operative pain.

Studies on Recombinant Human Bone Morphogenetic Protein 2 Loaded Nano-Hydroxyapatite/Silk Fibroin Scaffolds

2011 ◽  
Vol 175-176 ◽  
pp. 253-257 ◽  
Author(s):  
Yan Hong Zhang ◽  
Liang Jun Zhu ◽  
Ju Ming Yao
Keyword(s):  
Bone Formation ◽  
Bone Morphogenetic Protein ◽  
Silk Fibroin ◽  
Human Bone ◽  
Bone Morphogenetic Protein 2 ◽  
Morphogenetic Protein ◽  
Prokaryotic Expression System ◽  
Human Bone Morphogenetic Protein ◽  
Recombinant Human Bone

Bone Morphogenetic Protein 2 (BMP-2) is a member of the transforming growth factor superfamily. It plays an important role in stimulating osteoblast differentiation and bone formation, and has been widely utilized in clinical bone repairing by implantation. In this study, the nano-hydroxyapatite (nHA)/silk fibroin (SF) porous scaffolds were fabricated for the sustained delivery of recombinant human bone morphogenetic protein-2 (rhBMP-2), and then used to address the hypothesis that rhBMP-2 delivered from the scaffolds could enhance the bone formation in vitro. We optimized an effective method using a prokaryotic expression system to produce rhBMP-2. The rhBMP-2 was expressed, purified and renatured in vitro. And then the rhBMP-2 was loaded onto the nHA/SF scaffolds. The bioactivities of rhBMP-2-loaded nHA/SF scaffolds were assessed in vitro. The results showed that the rhBMP-2 promoted the osteoblasts adhesion and proliferation on the nHA/SF scaffolds. Also, the rhBMP-2 released from the nHA/SF scaffold stimulated a significant increase in alkaline phosphatase (ALP) activity of osteoblasts in vitro. These results demonstrated that the rhBMP-2-loaded nHA/SF scaffolds could promote the bone regeneration and showed potential applications in the bone tissue engineering.

scholarly journals The Bone Regeneration Capacity of BMP-2 + MMP-10 Loaded Scaffolds Depends on the Tissue Status

Pharmaceutics ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 979
Author(s):  
Patricia Garcia-Garcia ◽  
Ricardo Reyes ◽  
José Antonio Rodriguez ◽  
Tomas Martín ◽  
Carmen Evora ◽  
...  
Keyword(s):  
Bone Formation ◽  
Bone Regeneration ◽  
Growth Promotion ◽  
Tissue Growth ◽  
Bone Morphogenetic Protein 2 ◽  
Morphogenetic Protein ◽  
Therapeutic Molecules ◽  
Positive Effect

Biomaterials-mediated bone formation in osteoporosis (OP) is challenging as it requires tissue growth promotion and adequate mineralization. Based on our previous findings, the development of scaffolds combining bone morphogenetic protein 2 (BMP-2) and matrix metalloproteinase 10 (MMP-10) shows promise for OP management. To test our hypothesis, scaffolds containing BMP-2 + MMP-10 at variable ratios or BMP-2 + Alendronate (ALD) were prepared. Systems were characterized and tested in vitro on healthy and OP mesenchymal stem cells and in vivo bone formation was studied on healthy and OP animals. Therapeutic molecules were efficiently encapsulated into PLGA microspheres and embedded into chitosan foams. The use of PLGA (poly(lactic-co-glycolic acid)) microspheres as therapeutic molecule reservoirs allowed them to achieve an in vitro and in vivo controlled release. A beneficial effect on the alkaline phosphatase activity of non-OP cells was observed for both combinations when compared with BMP-2 alone. This effect was not detected on OP cells where all treatments promoted a similar increase in ALP activity compared with control. The in vivo results indicated a positive effect of the BMP-2 + MMP-10 combination at both of the doses tested on tissue repair for OP mice while it had the opposite effect on non-OP animals. This fact can be explained by the scaffold’s slow-release rate and degradation that could be beneficial for delayed bone regeneration conditions but had the reverse effect on healthy animals. Therefore, the development of adequate scaffolds for bone regeneration requires consideration of the tissue catabolic/anabolic balance to obtain biomaterials with degradation/release behaviors suited for the existing tissue status.

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