Bone morphogenetic proteins promote cartilage differentiation and protect engineered artificial cartilage from fibroblast invasion and destruction.
OBJECTIVE
An important role in joint and cartilage homeostasis in adults has been demonstrated recently for morphogenetic factors of the transforming growth factor beta family. Therefore, this study was undertaken to investigate the potential of bone morphogenetic proteins (BMPs) in chondrocyte differentiation using current technologies of tissue engineering.


METHODS
Complementary DNAs of recombinant human BMPs 2, 4, 5, 6, and 7 were transfected into primary bovine articular chondrocytes. Transgenic chondrocytes were assembled 3-dimensionally in alginate or in bioresorbable co-polymer fleeces of vicryl and polydioxanon embedded in low-melting-point agarose. Redifferentiation and formation of cartilage tissue in vitro or after subcutaneous transplantation into nude mice were assayed by semiquantitative reverse transcriptase-polymerase chain reaction, histology, and in situ hybridization, and findings were compared with those in unmodified or control-transfected primary chondrocytes.


RESULTS
Compared with other BMPs and control vector, BMP-7 induced a decrease in type I collagen expression in artificial cartilage, while transcription of the cartilage-specific type II collagen remained stable. In transplantation experiments, BMP-7 transgenic cartilage revealed the greatest amount of matrix synthesis, and BMP-7 was the only morphogen to suppress the infiltrative response of mouse fibroblastic cells into engineered cartilage, thereby preventing transplant destruction.


CONCLUSIONS
Cartilage differentiation and matrix maturation are promoted by BMPs in cartilage engineering. The inhibitory effect of BMP-7 on a nonspecific infiltrative response in immunocompromised nude mice further suggests that individual morphogens not only may contribute to cartilage maturation, but also may protect it from nonspecific inflammation and invasive destruction. These properties advance BMPs as promising tools for engineering of cartilaginous joint bioprostheses and as candidate biologic agents or genes for cartilage stabilization in arthritis.
Kaps
Christian
C
Charité University Hospital, Humboldt University of Berlin, Germany.
Bramlage
Carsten
C
Smolian
Heike
H
Haisch
Andreas
A
Ungethüm
Ute
U
Burmester
Gerd-R
GR
Sittinger
Michael
M
Gross
Gerhard
G
Häupl
Thomas
T
D000818:Animals; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D055417:Bone Morphogenetic Protein 5; D055418:Bone Morphogenetic Protein 6; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000235:genetics*; D002358:Cartilage, Articular / Q000166:cytology* / Q000637:transplantation; D002417:Cattle; D002450:Cell Communication / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology*; D005347:Fibroblasts / Q000166:cytology*; D015870:Gene Expression / Q000502:physiology; D006085:Graft Survival / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D023822:Tissue Engineering; D014162:Transfection; D016212:Transforming Growth Factor beta
C525718:BMP2 protein, human; C525809:BMP4 protein, human; C525814:BMP5 protein, human; C525816:BMP6 protein, human; C525819:BMP7 protein, human; C525719:Bmp2 protein, mouse; C525810:Bmp4 protein, mouse; C525815:Bmp5 protein, mouse; C525817:Bmp6 protein, mouse; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D055417:Bone Morphogenetic Protein 5; D055418:Bone Morphogenetic Protein 6; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D016212:Transforming Growth Factor beta