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Effect of Bone Morphogenetic Protein-2-Expressing Muscle-Derived Cells on Healing of Critical-Sized Bone Defects in Mice
Joon Yung Lee, MD; Douglas Musgrave, MD; Dalip Pelinkovic, MD; Kazumasa Fukushima, MD, PhD; James Cummins, BSc; Arvydas Usas, MD; Paul Robbins, PhD; Freddie H. Fu, MD; Johnny Huard, PhD
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Investigation performed at the Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania
Joon Yung Lee, MD
Douglas Musgrave, MD
Dalip Pelinkovic, MD
Kazumasa Fukushima, MD, PhD
James Cummins, BSc
Arvydas Usas, MD
Paul Robbins, PhD
Freddie H. Fu, MD
Johnny Huard, PhD
Growth and Development Laboratory, Department of Orthopaedic Surgery (J.Y.L., D.M., D.P., K.F., J.C., A.U., and J.H.) and Department of Molecular Genetics and Biochemistry (P.R. and J.H.), and Division of Sports Medicine, Department of Orthopaedic Surgery (F.H.F.), Children’s Hospital of Pittsburgh and University of Pittsburgh, Pittsburgh, PA 15261

No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. No funds were received in support of this study.

J Bone Joint Surg Am, 2001 Jul 01;83(7):1032-1039
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Abstract

Background: Cells that express bone morphogenetic protein-2 (BMP-2) can now be prepared by transduction with adenovirus containing BMP-2 cDNA. Skeletal muscle tissue contains cells that differentiate into osteoblasts on stimulation with BMP-2. The objectives of this study were to prepare BMP-2-expressing muscle-derived cells by transduction of these cells with an adenovirus containing BMP-2 cDNA and to determine whether the BMP-2-expressing muscle-derived cells would elicit the healing of critical-sized bone defects in mice.

Methods: Primary cultures of muscle-derived cells from a normal male mouse were transduced with adenovirus encoding the recombinant human BMP-2 gene (adBMP-2). These cells (5 ¥ 105) were implanted into a 5-mm-diameter critical-sized skull defect in female SCID (severe combined immunodeficiency strain) mice with use of a collagen sponge as a scaffold. Healing in the treatment and control groups was examined grossly and histologically at two and four weeks. Implanted cells were identified in vivo with use of the Y-chromosome-specific fluorescent in situ hybridization (FISH) technique, and their differentiation into osteogenic cells was demonstrated by osteocalcin immunohistochemistry.

Results: Skull defects treated with muscle cells that had been genetically engineered to express BMP-2 had >85% closure within two weeks and 95% to 100% closure within four weeks. Control groups in which the defect was not treated (group 1), treated with collagen only (group 2), or treated with collagen and muscle cells without adBMP-2 (group 3) showed at most 30% to 40% closure of the defect by four weeks, and the majority of the skull defects in those groups showed no healing. Analysis of injected cells in group 4, with the Y-chromosome-specific FISH technique showed that the majority of the transplanted cells were located on the surfaces of the newly formed bone, but a small fraction (approximately 5%) was identified within the osteocyte lacunae of the new bone. Implanted cells found in the new bone stained immunohistochemically for osteocalcin, indicating that they had differentiated in vivo into osteogenic cells.

Conclusions: This study demonstrates that cells derived from muscle tissue that have been genetically engineered to express BMP-2 elicit the healing of critical-sized skull defects in mice. The cells derived from muscle tissue appear to enhance bone-healing by differentiating into osteoblasts in vivo.

Clinical Relevance:Ex vivo gene therapy with muscle-derived cells that have been genetically engineered to express BMP-2 may be used to treat nonhealing bone defects. In addition, muscle-derived cells appear to include stem cells, which are easily obtained with muscle biopsy and could be used in gene therapy to deliver BMP-2.

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    Accreditation Statement
    These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
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