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The Journal of Bone and Joint Surgery (American) 85:1030-1039 (2003)
© 2003 The Journal of Bone and Joint Surgery, Inc.

Scientific Article

Mechanism of Bone Formation with Gene Transfer of the cDNA Encoding for the Intracellular Protein LMP-1

Akihito Minamide, MD, PhD, Scott D. Boden, MD, Manjula Viggeswarapu, PhD, Gregory A. Hair, PhD, Colleen Oliver, DVM and Louisa Titus, PhD

Investigation performed at the Department of Orthopaedic Surgery, Emory Spine Center, Emory University School of Medicine, Decatur, and the Atlanta Veterans Affairs Medical Center, Atlanta, Georgia

Akihito Minamide, MD, PhD
Scott D. Boden, MD
Manjula Viggeswarapu, PhD
Gregory A. Hair, PhD
Colleen Oliver, DVM
Louisa Titus, PhD
Department of Orthopaedic Surgery, Emory Spine Center, Emory University School of Medicine, 2165 North Decatur Road, Decatur, GA 30033. E-mail address for S.D. Boden: scott_boden{at}emoryhealthcare.org

In support of their research or preparation of this manuscript, one or more of the authors received grants or outside funding from Medtronic Sofamor Danek, Atlanta Research and Education Foundation, Veterans Affairs Medical Center Merit Award, Veterans Affairs Research Enhancement Award Program, and the ERC Program of the National Science Foundation Award EEC-9731643. In addition, one or more of the authors received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity (licensing agreement with Medtronic Sofamor Danek). No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

Background: LIM mineralization protein-1 (LMP-1), an intracellular protein, is thought to induce secretion of soluble factors that convey its osteoinductive activity. Although evidence suggests that LMP-1 may be a critical regulator of osteoblast differentiation in vitro and in vivo, little is known about its mechanism of action. The purpose of the present study was to identify candidates for the induced secreted factors and to describe the time sequence of histological changes during bone formation induced by LMP-1.

Methods: Human lung carcinoma (A549) cells were used to determine if LMP-1 overexpression would induce expression of bone morphogenetic proteins (BMPs) in vitro. Cultured A549 cells were infected with recombinant replication-deficient human type-5 adenovirus containing the LMP-1 or LacZ cDNA. Cells were subjected to immunohistochemical analysis after forty-eight hours. Finally, sixteen athymic rats received subcutaneous implants consisting of collagen disks loaded with human buffy-coat cells that were infected with one of the above two viruses. Rats were killed at intervals, and explants were studied with histological and immunohistochemical analyses.

Results: In vitro experiments with A549 cells showed that AdLMP-1-infected cells express elevated levels of BMP-2, BMP-4, BMP-6, BMP-7, and TGF-ß1 (transforming growth factor-beta 1) protein. Human buffy-coat cells infected with AdLMP-1 also demonstrated increased levels of BMP-4 and BMP-7 protein seventy-two hours after ectopic implantation in athymic rats, confirming the in vitro hypothesis.

Conclusions: The osteoinductive properties of LMP-1 involve synthesis of several BMPs and the recruitment of host cells that differentiate and participate in direct membranous bone formation.

Clinical Relevance: Ex vivo gene therapy with the LMP-1 cDNA-induced secretion of multiple BMPs may provide an alternative to implantation of large doses of a single BMP to induce new bone formation.



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