Haijun Tian1, Chen-Shuang Li2, Trevor P Scott3, Scott R Montgomery3, Kevin Phan3, Lifeng Lao3, Wei Zhang3, Yawei Li3, Tetsuo Hayashi3, Shinji Takahashi3, Raed Alobaidaan3, Monchai Ruangchainikom3, Ke-Wei Zhao4, Elsa J Brochmann5, Samuel S Murray5, Jeffrey C Wang6, Michael D Daubs7. 1. Department of Orthopaedic Surgery, Shanghai Changzheng Hospital, Second Military Medical University, 415 Fengyang Rd., Shanghai, 200003, P.R. China; Department of Orthopaedic Surgery, University of California, 675 Charles E. Young Dr. S., Los Angeles, CA 90024, USA. Electronic address: haijuntianmd@gmail.com. 2. Department of Orthodontics, Peking University School and Hospital of Stomatology, 22 South Zhongguancun St., Beijing 100081, P.R. China. 3. Department of Orthopaedic Surgery, University of California, 675 Charles E. Young Dr. S., Los Angeles, CA 90024, USA. 4. Research Service, VA Greater Los Angeles Healthcare System, 16111 Plummer St., North Hills, CA 91343, USA. 5. Research Service, VA Greater Los Angeles Healthcare System, 16111 Plummer St., North Hills, CA 91343, USA; Geriatric Research, Education and Clinical Center, VA Greater Los Angeles Healthcare System, 16111 Plummer St., North Hills, CA 91343, USA; Department of Medicine, University of California, 650 Charles E. Young Dr. S., Los Angeles, CA 90024, USA. 6. Department of Orthopaedic Surgery, Keck School of Medicine of USC, 1520 San Pablo, HCT Suite 2000, Los Angeles, CA 90033, USA. 7. Division of Orthopaedic Surgery, Department of Surgery, University of Nevada School of Medicine, 2040 W Charleston Blvd, Suite 601, Las Vegas, NV 89102, USA.
Abstract
BACKGROUND CONTEXT: Bone morphogenetic protein-2 (BMP-2) has been used to successfully promote spine fusion, but side-effects including nerve inflammation have been observed. PURPOSE: To investigate the direct neurotoxic effects of BMP-2 and test the hypotheses that the use of BMP binding proteins, such as secreted phosphoprotein 24 kD (Spp24), can reduce or eliminate these effects. STUDY DESIGN: In vitro experiments and in vivo analysis in a rodent model. METHODS: In vitro, dorsal root ganglion cells were cultured in the presence of BMP-2 with and without Spp24 and calcitonin gene-related peptide and Substance P, markers of neuroinflammation, were measured by immunohistochemistry. In vivo, rats underwent a left-sided laminotomy at L5 to expose the S1 nerve root and were randomized into four different groups according to the intervention at the laminotomy site: collagen sponge only (no BMP-2 or Spp24), BMP-2 in a collagen sponge only, BMP-2 in a collagen sponge+an empty collagen sponge to act as a barrier, and BMP-2 in a collagen sponge+Spp24 in a collagen sponge to act as a barrier. Functional evaluation was done using the Basso, Beattie, and Bresnahan scale and immunohistochemical analyses were performed using calcitonin gene-related peptide and Substance P staining. RESULTS: The neuroinflammatory effects of BMP-2 in vitro were ameliorated by the addition of Spp24. Similarly, in vivo, Spp24 reduced the expression of markers on neuroinflammation in animals treated with BMP-2 and also improved the function after BMP-2 administration. CONCLUSIONS: These results confirm that BMP binding proteins have great potential as adjuvant therapies to limit BMP-2 related side-effects in spine surgery.
BACKGROUND CONTEXT: Bone morphogenetic protein-2 (BMP-2) has been used to successfully promote spine fusion, but side-effects including nerve inflammation have been observed. PURPOSE: To investigate the direct neurotoxic effects of BMP-2 and test the hypotheses that the use of BMP binding proteins, such as secreted phosphoprotein 24 kD (Spp24), can reduce or eliminate these effects. STUDY DESIGN: In vitro experiments and in vivo analysis in a rodent model. METHODS: In vitro, dorsal root ganglion cells were cultured in the presence of BMP-2 with and without Spp24 and calcitonin gene-related peptide and Substance P, markers of neuroinflammation, were measured by immunohistochemistry. In vivo, rats underwent a left-sided laminotomy at L5 to expose the S1 nerve root and were randomized into four different groups according to the intervention at the laminotomy site: collagen sponge only (no BMP-2 or Spp24), BMP-2 in a collagen sponge only, BMP-2 in a collagen sponge+an empty collagen sponge to act as a barrier, and BMP-2 in a collagen sponge+Spp24 in a collagen sponge to act as a barrier. Functional evaluation was done using the Basso, Beattie, and Bresnahan scale and immunohistochemical analyses were performed using calcitonin gene-related peptide and Substance P staining. RESULTS: The neuroinflammatory effects of BMP-2 in vitro were ameliorated by the addition of Spp24. Similarly, in vivo, Spp24 reduced the expression of markers on neuroinflammation in animals treated with BMP-2 and also improved the function after BMP-2 administration. CONCLUSIONS: These results confirm that BMP binding proteins have great potential as adjuvant therapies to limit BMP-2 related side-effects in spine surgery.
Authors: Mandy E Turner; Christine A White; Sarah M Taylor; Kathryn Neville; Karen Rees-Milton; Wilma M Hopman; Michael A Adams; Tassos Anastassiades; Rachel M Holden Journal: Calcif Tissue Int Date: 2021-01-22 Impact factor: 4.333
Authors: Kendall Mitchell; Jill P Shah; Clifton L Dalgard; Lyubov V Tsytsikova; Ashley C Tipton; Anton E Dmitriev; Aviva J Symes Journal: BMC Neurosci Date: 2016-12-01 Impact factor: 3.288