Structural and functional healing of critical-size segmental bone defects by transduced muscle-derived cells expressing BMP4.
BACKGROUND
Our previous studies have shown that muscle-derived cells, including a population of muscle stem cells, transduced with a retroviral vector expressing bone morphogenetic protein 4 (BMP4) can improve the healing of critical-size calvarial defects. However, we did not evaluate the functionality of the healed bone. The purpose of this study was to determine whether primary muscle-derived cells transduced with retroBMP4 can heal a long bone defect both structurally and functionally.


METHODS
Primary muscle-derived cells were genetically engineered to express BMP4 and were implanted into 7-mm femoral defects created in syngeneic rats. Muscle-derived cells transduced with retroLacZ were used in the control group. Bone healing was monitored by radiography, histology, and biomechanical testing at designated time points.


RESULTS
Most of the defects treated with muscle-derived cells expressing BMP4 formed bridging callous by 6 weeks after surgery, and exhibited radiographically evident union at 12 weeks after cell implantation. Histological analysis at 12 weeks revealed that the medullary canal of the femur was restored and the cortex was remodeled between the proximal and distal ends of each BMP4-treated defect. In contrast, the defects treated with muscle-derived cells expressing beta-galactosidase displayed nonunion at all tested time points. An evaluation of the maximum torque-to-failure in the treatment group indicated that the healed bones possessed 77 +/- 28% of the strength of the contralateral intact femora. Torsional stiffness and energy-to-failure were not significantly different between the treated and intact limbs.


CONCLUSIONS
This study demonstrated that primary muscle-derived cells transduced with retroBMP4 can elicit both structural and functional healing of critical-size segmental long bone defects created in rats.
Shen
Hsain-Chung
HC
Growth and Development Laboratory, Children's Hospital of Pittsburgh, Pittsburgh, PA 15213-2583, USA.
Peng
Hairong
H
Usas
Arvydas
A
Gearhart
Brian
B
Fu
Freddie H
FH
Huard
Johnny
J
D000818:Animals; D001847:Bone Diseases / Q000628:therapy*; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000235:genetics* / Q000627:therapeutic use; D002146:Bony Callus / Q000254:growth & development; D005269:Femur / Q000000981:diagnostic imaging / Q000293:injuries / Q000473:pathology; D017102:Fracture Healing; D050723:Fractures, Bone / Q000000981:diagnostic imaging / Q000473:pathology / Q000628:therapy; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000627:therapeutic use; D008297:Male; D032342:Muscle Cells / Q000637:transplantation*; D010012:Osteogenesis / Q000235:genetics / Q000502:physiology; D011859:Radiography; D051381:Rats; D011916:Rats, Inbred F344; D012190:Retroviridae / Q000235:genetics
C525811:Bmp4 protein, rat; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins