The inductive effect of bone morphogenetic protein-4 on chondral-lineage differentiation and in situ cartilage repair.
OBJECTIVE
As recent studies have suggested that bone morphogenetic protein-4 (BMP-4) and BMP-7 are promising cartilage differentiation factors, this study aimed to compare the efficacy of BMP-4 and BMP-7 for chondral-lineage differentiation in vitro as well as the efficacy of BMP-4 for articular cartilage repair in vivo.


METHODS
Rabbit mesenchymal stromal cells and articular chondrocytes were treated with 10 ng/mL human recombinant BMP-4 or BMP-7. The expression of cartilage-specific genes (col II, aggrecan, and Sox9) and fibroblast growth factor receptor genes was tested by real-time polymerase chain reaction in vitro. Also, full-thickness cartilage defects (diameter 4 mm, thickness 3 mm) were created in New Zealand white rabbits and untreated (group I), or treated with a bilayer collagen scaffold (group II) or BMP-4 with scaffold (group III) (n = 12/group). The repaired tissues were harvested for histology and mechanical testing after 6 or 12 weeks.


RESULTS
Cartilage differentiation of mesenchymal stromal cells was more apparent after BMP-4 treatment, as evidenced by higher expression of type II collagen and aggrecan genes. Also, BMP-4 induced higher aggrecan and fibroblast growth factor receptor-2 gene expression in chondrocytes, whereas BMP-7 had no effect. In the in vivo experiments, group III treated with BMP-4 protein had the largest amounts of cartilage tissue, which restored a greater surface area of the defect and achieved higher International Cartilage Repair Society scores. Moreover, Young's modulus, which indicates the mechanical properties of the repaired tissue, was markedly higher in group III than in groups I and II (p < 0.05), but lower than in normal tissue.


CONCLUSIONS
BMP-4 is more potent than BMP-7 for cartilage differentiation. The delivery of BMP-4 protein in a bilayer collagen scaffold stimulates the formation of cartilage tissue.
Jiang
YangZi
Y
Center for Stem Cell and Tissue Engineering, Zhejiang University, Hangzhou, China.
Chen
Long Kun
LK
Zhu
Ding Cheng
DC
Zhang
Guo Rong
GR
Guo
Chao
C
Qi
Yi Ying
YY
Ouyang
Hong Wei
HW
D000818:Animals; D001696:Biomechanical Phenomena / Q000187:drug effects; D055415:Bone Morphogenetic Protein 4 / Q000494:pharmacology*; D002358:Cartilage, Articular / Q000187:drug effects* / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects*; D019070:Cell Lineage / Q000187:drug effects*; D019902:Chondrocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008855:Microscopy, Electron, Scanning; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D011994:Recombinant Proteins / Q000494:pharmacology; D034421:Sus scrofa; D054457:Tissue Scaffolds / Q000737:chemistry; D014945:Wound Healing / Q000187:drug effects*
C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; D016326:Extracellular Matrix Proteins; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins