title: Intradiscal injection of simvastatin results in radiologic, histologic, and genetic evidence of disc regeneration in a rat model of degenerative disc disease.
abstract: BACKGROUND
  A 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.
  
  
  OBJECTIVE
  The purpose of the present study was to develop a novel conservative treatment for DDD and related discogenic back pain.
  
  
  METHODS
  The setting of this study is the laboratory investigation.
  
  
  METHODS
  Disc 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.
  
  
  RESULTS
  Radiologically, 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.
  
  
  CONCLUSIONS
  Degenerate 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.
authors.affiliation: Department of Neurosurgery, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA.
authors.forename: Khoi D
authors.initials: KD
authors.lastname: Than
authors.affiliation: Department of Neurosurgery, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA.
authors.forename: Shayan U
authors.initials: SU
authors.lastname: Rahman
authors.affiliation: Department of Neurosurgery, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: University of Michigan Medical School, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Khan
authors.affiliation: University of Michigan Medical School, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA.
authors.forename: Kwaku A
authors.initials: KA
authors.lastname: Kyere
authors.affiliation: Department of Neurosurgery, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA.
authors.forename: Tracey T
authors.initials: TT
authors.lastname: Than
authors.affiliation: Department of Neurosurgery, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA.
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Miyata
authors.affiliation: Department of Pharmaceutical Sciences, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA.
authors.forename: Yoon-Shin
authors.initials: YS
authors.lastname: Park
authors.affiliation: Department of Neurosurgery, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: La Marca
authors.affiliation: Department of Biostatistics, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA.
authors.forename: Hyungjin M
authors.initials: HM
authors.lastname: Kim
authors.affiliation: Department of Neurosurgery, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA.
authors.forename: Huina
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Park
authors.affiliation: Department of Neurosurgery, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA. Electronic address: lincy@umich.edu.
authors.forename: Chia-Ying
authors.initials: CY
authors.lastname: Lin
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007278:Injections, Spinal; D007403:Intervertebral Disc / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D055959:Intervertebral Disc Degeneration / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012038:Regeneration / Q000187:drug effects* / Q000502:physiology; D019821:Simvastatin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D055396:Bone Morphogenetic Protein 2; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin
keywords: BMP-2; Back pain; Degenerative disc disease; Discogenic back pain; Rodent model; Simvastatin