title: Bone morphogenetic protein-2-mediated pain and inflammation in a rat model of posterolateral arthrodesis.
abstract: Bone morphogenetic protein-2 (BMP-2) is a pleiotropic, secreted molecule with diverse effects. The potent ability of BMP-2 to stimulate bone growth prompted its widespread clinical use for arthrodesis (spine fusion). However, elevated post-operative pain in patients treated with BMP-2 has been increasingly reported. Determining whether BMP-2 induces pain directly or whether it induces neuroinflammation, which could lower the threshold for pain, is important for developing therapeutic interventions. We therefore modeled the clinical use of BMP-2 for posterior lumbar fusion by implanting absorbable collagen sponges soaked with either recombinant human BMP-2 (rhBMP-2) or vehicle above the L4-L5 transverse processes of rat spine.
  
  
  
  Using microarray analysis we found that implantation of rhBMP-2-soaked absorbable collagen sponges resulted in altered expression of numerous pro-inflammatory genes in the adjacent dorsal root ganglia (DRG) showing that implantation of rhBMP-2/absorbable collagen sponges triggers potent neuroinflammatory responses in the DRG-2. Interestingly, direct BMP-2 treatment of DRG explants resulted in changes in gene expression that were not specifically pro-inflammatory. Rats implanted with rhBMP-2 in absorbable collagen sponges also exhibited a transient change in thermal and mechanical sensitivity indicating that rhBMP-2 applied to the lumbar spine could increase pain sensitivity. Immunohistochemical analysis indicated macrophage infiltration in the DRG and spinal nerve in rats implanted with rhBMP-2/absorbable collagen sponges or absorbable collagen sponges alone, but not in rats that underwent surgery without implantation of the absorbable collagen sponges suggesting that the sponges contributed to the biological response. Indeed, analysis of DRGs taken from rats implanted with absorbable collagen sponges without rhBMP-2 showed a significant change in gene expression distinct from DRGs from rats undergoing surgery only.
  
  
  
  Our data indicate that implantation of rhBMP-2/absorbable collagen sponges on the lumbar spine triggers potent neuroinflammatory responses in the DRG. Importantly, however, these BMP-2 effects may be partially mediated through a response to the absorbable collagen sponges.
authors.affiliation: Department of Pharmacology and Molecular Therapeutics, Uniformed Services University, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA.
authors.forename: Kendall
authors.initials: K
authors.lastname: Mitchell
authors.affiliation: Department of Pharmacology and Molecular Therapeutics, Uniformed Services University, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA.
authors.forename: Jill P
authors.initials: JP
authors.lastname: Shah
authors.affiliation: Department of Anatomy, Physiology and Genetics, Uniformed Services University, Bethesda, MD, USA.
authors.forename: Clifton L
authors.initials: CL
authors.lastname: Dalgard
authors.affiliation: Department of Pharmacology and Molecular Therapeutics, Uniformed Services University, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA.
authors.forename: Lyubov V
authors.initials: LV
authors.lastname: Tsytsikova
authors.affiliation: Department of Pharmacology and Molecular Therapeutics, Uniformed Services University, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA.
authors.forename: Ashley C
authors.initials: AC
authors.lastname: Tipton
authors.affiliation: Department of Surgery, Uniformed Services University, Bethesda, MD, USA.|Department of Orthopaedic Surgery, Walter Reed National Military Medical Center, Bethesda, MD, 20814, USA.|Division of Applied Mechanics, CDRH/OSEL, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA.
authors.forename: Anton E
authors.initials: AE
authors.lastname: Dmitriev
authors.affiliation: Department of Pharmacology and Molecular Therapeutics, Uniformed Services University, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA. Aviva.symes@usuhs.edu.
authors.forename: Aviva J
authors.initials: AJ
authors.lastname: Symes
mesh_terms: D020341:Absorbable Implants / Q000009:adverse effects; D000818:Animals; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000009:adverse effects*; D055396:Bone Morphogenetic Protein 2 / Q000008:administration & dosage / Q000009:adverse effects*; D003094:Collagen / Q000009:adverse effects; D004343:Drug Implants / Q000009:adverse effects; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D008159:Lumbar Vertebrae / Q000601:surgery*; D023421:Models, Animal; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D010149:Postoperative Pain / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects; D013123:Spinal Fusion; D015503:Surgical Sponges / Q000009:adverse effects; D046509:Tissue Culture Techniques
chemical_list: C525718:BMP2 protein, human; D050071:Bone Density Conservation Agents; D055396:Bone Morphogenetic Protein 2; D004343:Drug Implants; D011994:Recombinant Proteins; D003094:Collagen
keywords: Bone morphogenetic protein-2; Cytokines; Dorsal root ganglia; Hyperalgesia; Inflammation; Macrophages