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Transduced Bovine Articular Chondrocytes Affect the Metabolism of Cocultured Nucleus Pulposus Cells In Vitro: Implications for Chondrocyte Transplantation Into the Intervertebral Disc

Zhang, Yejia MD, PhD*†; Li, Zhen MD*; Thonar, Eugene J.-M. A. PhD*‡§; An, Howard S. MD*; He, Tong-Chuan MD, PhD; Pietryla, Daniel BS; Phillips, Frank M. MD*

doi: 10.1097/01.brs.0000187880.39298.f0
Basic Science

Study Design. Biologic study on the effects of coculture of bovine articular chondrocytes transduced ex vivo with genes expressing bone morphogenetic proteins (BMPs) on nucleus pulposus (NP) cells.

Objective. To evaluate the effects of bovine articular chondrocytes transduced with adenoviruses expressing various BMPs on proteoglycan and collagen production, and cellular proliferation of NP cells in vitro.

Summary of Background Data. Matrix synthesis by intervertebral disc cells is promoted by exposing the cells to growth factors or delivering genes that permit sustained expression of growth factors. We propose a novel therapeutic approach involving delivery of autologous chondrocytes, transduced ex vivo with bioactive proteins, to provide both the cells and proteins required to stimulate disc healing.

Methods. Adult bovine articular chondrocytes were transduced with adenoviruses (Ads) expressing either BMP-2, 4, 5, 7, 10, or 13 and plated as monolayers. Bovine NP cells encapsulated in alginate beads were cocultured, floating in the medium. Proteoglycan and collagen accumulation, and NP cell proliferation were measured after 6 days of coculture. As a positive control, beads were cocultured with articular chondrocytes in the presence of rhBMP-7.

Results: NP cells cocultered with articular chondrocytes transduced with BMPs-2, 4, 7, and 10 accumulated significantly (P < 0.05) more proteoglycan than when cocultured with chondrocytes transduced with AdGFP (control) [AdBMP-2: 23.6%; AdBMP-4: 27.0%; AdBMP-7: 129.1%; AdBMP-10: 102.1% increases respectively]. Collagen accumulation was significantly (P < 0.05) increased by NP cells cocultured with articular chondrocytes transduced with BMPs-2, 4, 5, and 7. [AdBMP-2: 104.6%; AdBMP-4: 40.6%; AdBMP-5: 58.6%; AdBMP-7: 55.5% increases respectively]. NP cells proliferated when cocultured with articular chondrocytes transduced with AdBMP-2 and -7.

Conclusions: Bovine NP cells are stimulated to produce proteoglycans and collagen when exposed to chondrocytes transduced with genes for various BMPs. If applied to the treatment of disc degeneration, this strategy could provide the disc with not only metabolically active chondrocytes but also promote matrix replenishment by stimulating native NP cells.

We propose a novel therapeutic approach involving the delivery of autologous chondrocytes transduced ex vivo with genes for bioactive proteins to provide both the cells and proteins required to stimulate intervertebral disc healing. We show that bovine nucleus pulposus cells are stimulated in vitro to produce proteoglycans and collagen, and proliferate when they are cocultured with autologous chondrocytes transduced with genes for various bone morphogenetic proteins. Articular chondrocytes transduced with adenovirus expressing bone morphogenetic protein-2 and 7 were most effective in promoting nucleus pulposus collagen and proteoglycan production, respectively.

From the Departments of *Orthopedic Surgery, †Physical Medicine and Rehabilitation, ‡Biochemistry, and §Internal Medicine, Rush University Medical Center; and ∥Orthopedic Surgery, The University of Chicago, Chicago, IL.

Acknowledgment date: November 2, 2004. First revision date: April 18, 2005. Acceptance date: May 2, 2005.

Dr. Yejia Zhang is supported by the NICHHD (2K12 HD0197-7) through the Rehabilitation Medicine Scientist Training Program (RMSTP). This work was supported in part by NIH grants 1-P50-AR48152 and a grant from Stryker Biotech, Inc. Stryker Biotech, Inc. provided human recombinant OP-1.

The device(s)/drug(s) that is/are the subject of this manuscript is/are not FDA- approved for this indication and is/are not commercially available in the United States.

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

Address correspondence and reprint requests to Frank M. Phillips, MD, Midwest Orthopaedics, Suite 1063, 1725 W. Harrison Street, Chicago IL 60612; E-mail:

© 2005 Lippincott Williams & Wilkins, Inc.