Shingo Miyazaki1,2, Ashish D Diwan3, Kenji Kato1,4, Kevin Cheng1, Won C Bae5, Yang Sun6,7, Junichi Yamada1,8, Carol Muehleman9, Mary E Lenz1, Nozomu Inoue10, Robert L Sah1,6, Mamoru Kawakami11, Koichi Masuda12. 1. Department of Orthopaedic Surgery, University of California-San Diego, 9500 Gilman Dr., MC0863, La Jolla, CA, 92093-0863, USA. 2. Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho Chuo-Ku, Kobe, 650-0017, Hyogo, Japan. 3. Orthopaedic Research Institute and Department of Orthopaedic Surgery, St George Hospital, University of New South Wales, Suite 16, Lvl 5, 1 South Street, Kogarah, Sydney, NSW 2217, Australia. 4. Department of Orthopaedic Surgery, Nagoya City University Graduate School of Medicine, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Aichi, Japan. 5. Department of Radiology, University of California-San Diego, 9500 Gilman Dr., MC0997, La Jolla, CA, 92093-0997, USA. 6. Department of Bioengineering, University of California-San Diego, 9500 Gilman Dr., MC0412, La Jolla, CA, 92093-0412, USA. 7. Orthopaedic Medical Center, the Second Hospital of Jilin University, Changchun, Jilin, China. 8. Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, 514-8507, Mie, Japan. 9. Department of Biochemistry, Rush University Medical Center, 1645 W Harrison St, 5th floor, Chicago, 60612, IL, USA. 10. Department of Orthopaedic Surgery, Rush University Medical Center, 1611 W. Harrison St. Suite 204J, Chicago, 60612, IL, USA. 11. Spine Care Center, Wakayama Medical University Kihoku Hospital, 219, Myouji, Katsuragicho, Ito Gun, 649-7113, Wakayama, Japan. 12. Department of Orthopaedic Surgery, University of California-San Diego, 9500 Gilman Dr., MC0863, La Jolla, CA, 92093-0863, USA. komasuda@ucsd.edu.
Abstract
PURPOSE: To elucidate the effects of growth differentiation factor-6 (GDF6) on: (i) gene expression of inflammatory/pain-related molecules and structural integrity in the rabbit intervertebral disc (IVD) degeneration model, and (ii) sensory dysfunction and changes in pain-marker expression in dorsal nerve ganglia (DRGs) in the rat xenograft radiculopathy model. METHODS: Forty-six adolescent rabbits received anular-puncture in two non-consecutive lumbar IVDs. Four weeks later, phosphate-buffered saline (PBS) or GDF6 (1, 10 or 100 µg) was injected into the nucleus pulposus (NP) of punctured discs and followed for 4 weeks for gene expression analysis and 12 weeks for structural analyses. For pain assessment, eight rabbits were sacrificed at 4 weeks post-injection and NP tissues of injected discs were transplanted onto L5 DRGs of 16 nude rats to examine mechanical allodynia. The rat DRGs were analyzed immunohistochemically. RESULTS: In GDF6-treated rabbit NPs, gene expressions of interleukin-6, tumor necrosis factor-α, vascular endothelial growth factor, prostaglandin-endoperoxide synthase 2, and nerve growth factor were significantly lower than those in the PBS group. GDF6 injections resulted in partial restoration of disc height and improvement of MRI disc degeneration grades with statistical significance in rabbit structural analyses. Allodynia induced by xenograft transplantation of rabbit degenerated NPs onto rat DRGs was significantly reduced by GDF6 injection. Staining intensities for ionized calcium-binding adaptor molecule-1 and calcitonin gene-related peptide in rat DRGs of the GDF6 group were significantly lower than those of the PBS group. CONCLUSION: GDF6 injection may change the pathological status of degenerative discs and attenuate degenerated IVD-induced pain.
PURPOSE: To elucidate the effects of growth differentiation factor-6 (GDF6) on: (i) gene expression of inflammatory/pain-related molecules and structural integrity in the rabbit intervertebral disc (IVD) degeneration model, and (ii) sensory dysfunction and changes in pain-marker expression in dorsal nerve ganglia (DRGs) in the rat xenograftradiculopathy model. METHODS: Forty-six adolescent rabbits received anular-puncture in two non-consecutive lumbar IVDs. Four weeks later, phosphate-buffered saline (PBS) or GDF6 (1, 10 or 100 µg) was injected into the nucleus pulposus (NP) of punctured discs and followed for 4 weeks for gene expression analysis and 12 weeks for structural analyses. For pain assessment, eight rabbits were sacrificed at 4 weeks post-injection and NP tissues of injected discs were transplanted onto L5 DRGs of 16 nude rats to examine mechanical allodynia. The rat DRGs were analyzed immunohistochemically. RESULTS: In GDF6-treated rabbit NPs, gene expressions of interleukin-6, tumor necrosis factor-α, vascular endothelial growth factor, prostaglandin-endoperoxide synthase 2, and nerve growth factor were significantly lower than those in the PBS group. GDF6 injections resulted in partial restoration of disc height and improvement of MRI disc degeneration grades with statistical significance in rabbit structural analyses. Allodynia induced by xenograft transplantation of rabbit degenerated NPs onto rat DRGs was significantly reduced by GDF6 injection. Staining intensities for ionizedcalcium-binding adaptor molecule-1 and calcitonin gene-related peptide in rat DRGs of the GDF6 group were significantly lower than those of the PBS group. CONCLUSION:GDF6 injection may change the pathological status of degenerative discs and attenuate degenerated IVD-induced pain.
Entities:
Keywords:
Growth differentiation factor-6; Inflammatory cytokines; Intervertebral disc degeneration; Pain behavior; Rabbit anular-puncture model; Rat xenograft radiculopathy model
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