(2005) Immune response and effect of adenovirus-mediated human BMP-2 gene transfer on the repair of segmental tibial bone defects in goats, Acta Orthopaedica, 76:5, 637-646, DOI: 10.1080 Background Tissue-engineered bone may be used for filling bone defects. There are, however, no reports on this technique used in large animals.Methods We evaluated the effectiveness of, and immune response in repairing diaphyseal bone defects by gene transfer using bone morphogenetic proteins (BMPs). We used adenovirus-mediated human BMP-2 (Adv-hBMP-2) gene-transduced bone marrow stromal cells (BMSCs) to repair 2.1-cm segmental tibial bone defects in goats (group I, n = 7). An Adv-ßgal-transduced BMSC group (group II, n = 5), a non-transduced BMSC group (group III, n = 5), and an untreated group (group IV, n = 2) were used as controls. Self-secreted extracellular matrix was used as cellular carrier.Results Radiographic and histomorphometric examination demonstrated more callus in the bone defects of group I compared to other groups.Week 24 after implantation, the defect healing rates of groups I, II, III, and IV were 6/7, 1/5, 2/5, and 0/2, respectively. The maximum compressive strength of new tissue in the bone defects of group I was higher than those of groups II and III. Temporary cellular and persistent humoral immune responses against adenovirus were detected after hBMP-2 gene transfer.Interpretation We found that Adv-hBMP-2 genetransduced BMSCs had superior osteoinductivity in the repair of tibial bone defects in goats, but it could cause temporary cellular and persistent humoral immune responses against adenovirus.

To better understand the effects of scaffold materials for bone morphogenetic protein 2 (BMP-2) genetic tissue engineering in vivo, several gels, including alginate, collagen, agarose, hyaluronate, fibrin, or Pluronic, were mixed with adenovirus-mediated human BMP-2 gene (Adv-hBMP-2) transduced bone marrow stromal cells (BMSCs) and injected into the muscles of athymic mice to evaluate the resulting osteogenesis and chondrogenesis. These gel and gene-transduced BMSC mixtures were also loaded onto beta-TCP/HAP biphasic calcined bone (BCB) and observed under scanning electron microscopy (SEM). In addition, these composite scaffolds were implanted into the subcutaneous site of athymic mice to construct tissue-engineered bone. After injection, collagen, hyaluronate, or alginate gel mixed with gene-transduced BMSCs induced more bone formation than a cell suspension in alpha-MEM. The agarose-gene-transduced BMSC gel was found to contain much more hyaline cartilage. SEM showed the BMSCs could survive in alginate, agarose, and collagen gel in vitro for up to 8 d. After implantation of tissue-engineered bone, the alginate, collagen, and agarose gel could promote new bone formation within a BCB in vivo. Little or no bone formed after injection of fibrin or Pluronic gel mixed with BMSCs or implantation with BCB. These findings help to elucidate the effects of various scaffold materials for future research in orthopedic tissue engineering using BMP-2 transduced cells.

Fenofibrate, as a lipid-lowering drug, has been reported to have a protective effect on the retina independent with plasma lipid levels. This study aimed to investigate that the ameliorative effects of fenofibrate on systemic and retinal inflammation, as well as gut microbiota dysbiosis in high-fat diet (HFD)-induced mice. C57BL/6J mice were randomly allocated into four groups: standard diet (SD) group; HFD group; SD plus fenofibrate (SD_ Fe) group; HFD plus fenofibrate (HFD_ Fe) group. After successfully establishing models (5 months), indicators associated with lipid, gut barrier, inflammation and gut microbiota were investigated. Our results showed that supplementing the HFD with fenofibrate decreased body weight gain, alleviated dyslipidemia and reversed the downregulation of short-chain fatty acid (SCFAs) in serum, retina and feces. Fenofibrate ameliorated intestinal barrier function damage in HFD-induced mice. Fenofibrate coadministration inhibited the levels of inflammatory factor and lipopolysaccharide (LPS) in the serum and attenuated inflammatory response in the retina of HFD-induced mice. Systemic LPS was positively correlated with a series of inflammatory factors in serum and retina, respectively. Fenofibrate supplementation down-regulated the abundances of LPS-associated bacteria in HFD mice, including Firmicutes and Proteobacteria at the phylum level, Desulfovibrionaceae at the family level, as well as unclassified_ Desulfovibrionaceae, Acetatifactor, Flavonifractor, Oscillibacter and Anaerotruncus at the genus level. However, fenofibrate treatment up-regulated the abundances of SCFA-associated bacteria in HFD mice, including Bacteroidetes at the phylum level, Porphyromonadaceae at the family level, as well as unclassified_Porphyromonadaceae, Barnesiella, Alloprevotella and Bifidobacterium at the genus level. In conclusion, our results confirmed fenofibrate could attenuate HFD-induced systemic and retinal inflammation, accompanying with restoration of intestinal barrier damage and modulation of gut microbiota/metabolites. This work provided an explanation for the ameliorative effects of fenofibrate on HFD-induced systemic and retinal inflammation might be partially related with the modulation of gut microbiota and its metabolites.

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