Intradiscal injection of simvastatin results in radiologic,histologic, and genetic evidence of disc regeneration in a rat model of degenerative disc disease |
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| Authors: | Khoi D Than Shayan U Rahman Lin Wang Adam Khan Kwaku A Kyere Tracey T Than Yoshinari Miyata Yoon-Shin Park Frank La Marca Hyungjin M Kim Huina Zhang Paul Park Chia-Ying Lin |
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| Institution: | 1. Department of Neurosurgery, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA;2. University of Michigan Medical School, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA;3. Department of Pharmaceutical Sciences, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA;4. Department of Biostatistics, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA;1. Department of Plastic, Reconstructive and Hand Surgery, Erasmus MC, University Medical Center, Rotterdam, The Netherlands;2. Department of Rehabilitation Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands;1. Applied Toxicology and Gene Therapy Pharmacology/Toxicology Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico, USA;2. Rehabilitation Medicine Research Center, Mayo Clinic, Rochester, Minnesota, USA;3. Gene Therapy Center, University of North Carolina, Chapel Hill, North Carolina, USA;4. Division of Pre-Clinical Innovations, National Center for Advancing Translational Sciences, NIH, Bethesda, Maryland, USA;2. Biomedical Research Centre, Sheffield Hallam University, Sheffield, UK;3. Transplant Immunology, St James''s University Hospital, Leeds, UK;4. Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK;1. King''s Thrombosis Centre, Department of Haematological Medicine, London, United Kingdom;2. Department of Acute Medicine, King''s College Hospital NHS Foundation Trust, London, United Kingdom |
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| Abstract: | Background contextA large percentage of back pain can be attributed to degeneration of the intervertebral disc (IVD). Bone morphogenetic protein 2 (BMP-2) is known to play an important role in chondrogenesis of the IVD. Simvastatin is known to upregulate expression of BMP-2. Thus, we hypothesized that intradiscal injection of simvastatin in a rat model of degenerative disc disease (DDD) would result in retardation of DDD.PurposeThe purpose of the present study was to develop a novel conservative treatment for DDD and related discogenic back pain.Study design/settingThe setting of this study is the laboratory investigation.MethodsDisc injury was induced in 272 rats via 21-ga needle puncture. After 6 weeks, injured discs were treated with simvastatin in a saline or hydrogel carrier. Rats were sacrificed at predetermined time points. Outcome measures assessed were radiologic, histologic, and genetic. Radiologically, the magnetic resonance imaging (MRI) index (number of pixels multiplied by the corresponding image densities) was determined. Histologically, disc spaces were read by three blinded scorers using a previously described histologic grading scale. Genetically, nuclei pulposi were harvested, and polymerase chain reaction was run to determine relative levels of aggrecan, collagen type II, and BMP-2 gene expression.ResultsRadiologically, discs treated with 5 mg/mL of simvastatin in hydrogel or saline demonstrated MRI indices that were normal through 8 weeks after treatment, although this was more sustained when delivered in hydrogel. Histologically, discs treated with 5 mg/mL of simvastatin in hydrogel demonstrated improved grades compared with discs treated at higher doses. Genetically, discs treated with 5 mg/mL of simvastatin in hydrogel demonstrated higher gene expression of aggrecan and collagen type II than control.ConclusionsDegenerate discs treated with 5 mg/mL of simvastatin in a hydrogel carrier demonstrated radiographic and histologic features resembling normal noninjured IVDs. In addition, the gene expression of aggrecan and collagen type II (important constituents of the IVD extracellular matrix) was upregulated in treated discs. Injection of simvastatin into degenerate IVDs may result in retardation of disc degeneration and represents a promising investigational therapy for conservative treatment of DDD. |
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| Keywords: | Back pain BMP-2 Degenerative disc disease Rodent model Simvastatin Discogenic back pain |
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