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Adverse events and bone morphogenetic protein-2
802
Letters to the Editor / The Spine Journal 11 (2011) 800–805
Adverse events and bone morphogenetic protein-2
To the Editor: Recently, a number of adverse events have been reported in the use of recombinant bone morphogenetic protein-2 (BMP-2) in spinal fusion [1–4]. We have been studying new bone formation after delivery of physiologic levels of BMP-2 using a cell therapy approach and have found this to rely on very selective neurogenic inflammation. We would like to suggest that this is actually a normal physiologic event in bone formation and fracture repair rather than an adverse event associated with delivery of this protein. First, our studies using BMP-2 have shown that neurogenic inflammation is one of the first steps necessary for bone formation [5,6]. Further, it appears that inhibition of this neuroinflammatory mechanism actually suppresses bone formation, further substantiating this connection. However, the exact mechanism remains uncertain. It may simply be that neurogenic inflammation is needed for innervation of the newly forming bone, most likely through axonal growth that requires nerve remodeling for sprouting. Alternatively, we have recently shown that peripheral nerves likely supply osteogenic cells [6]. Moreover, similar findings have been associated with fracture repair [7,8], where no exogenous BMPs are added. In these studies, peripheral nerves and release of neurogenic inflammatory mediators have been shown to play a critical role, with suppression of these factors blocking the bone healing [9]. Although both processes appear remarkably similar, it is unclear whether they are identical; however, this certainly raises the question of the role of the peripheral nervous system in bone formation and repair. Our data clearly suggest that nerve remodeling may be a normal physiologic process involved either directly or indirectly in new bone formation. Although more study is required to determine whether BMP-2 is launching an aberrant process or invoking this normal mechanism, the data clearly suggest that we should be careful in drawing conclusions prematurely. These facts drive home the point that a great deal more knowledge is needed on the mechanism of BMP-2 action in bone formation. It is now known that the brain is a central controller of bone homeostasis [10]. We suggest that it also controls bone repair but does so using the peripheral nervous system. We suggest that BMP-2 coordinates not only new bone formation and its ultimate fusion to preexisting skeletal bone in the event of fracture but also its innervation and vascular supply, without which it cannot be sustained.
References [1] Kang JD. Commentary: Another complication associated with rhBMP-2? Spine J 2011;11:517–9. [2] Smoljanovic T, Bojanic I. Commentary: An evolving perception of the risk of rhBMP-2 use for anterior spinal interbody fusions. Spine J 2011;11:520–1.
[3] Carragee EJ, Mitsunaga KA, Hurwitz EL, Scuderi GJ. Retrograde ejaculation after anterior lumbar interbody fusion using rhBMP-2: a cohort controlled study. Spine J 2011;11:511–6. [4] Dmitriev AE, Farhang S, Lehman RA Jr, et al. Bone morphogenetic protein-2 used in spinal fusion with spinal cord injury penetrates intrathecally and elicits a functional signaling cascade. Spine J 2010;10:16–25. [5] Salisbury E, Sonnet C, Heggeness M, et al. Heterotopic ossification has some nerve. Crit Rev Eukaryot Gene Expr 2010;20:313–24. [6] Salisbury E, Rodenberg E, Sonnet C, et al. Sensory nerve induced inflammation contributes to heterotopic ossification. J Cell Biochem 2011. [Epub ahead of print]. [7] Hukkanen M, Konttinen YT, Santavirta S, et al. Rapid proliferation of calcitonin gene-related peptide-immunoreactive nerves during healing of rat tibial fracture suggests neural involvement in bone growth and remodelling. Neuroscience 1993;54:969–79. [8] Li J, Kreicbergs A, Bergstrom J, et al. Site-specific CGRP innervation coincides with bone formation during fracture healing and modeling: a study in rat angulated tibia. J Orthop Res. 2007;25:1204–12. [9] Apel PJ, Crane D, Northam CN, et al. Effect of selective sensory denervation on fracture-healing: an experimental study of rats. J Bone Joint Surg Am 2009;91:2886–95. [10] Driessler F, Baldock PA. Hypothalamic regulation of bone. J Mol Endocrinol 2010;45:175–81.
Elizabeth A. Salisbury, BS Elizabeth A. Olmsted-Davis, PhD Alan R. Davis, PhD Houston, TX, USA FDA device/drug status: Not applicable. Author disclosures: EAS: Nothing to disclose. EAO-D: Nothing to disclose. ARD: Nothing to disclose. doi:10.1016/j.spinee.2011.07.017
Dmitriev et al. respond We appreciate the interest in our work by Salisbury et al. The role of bone morphogenetic protein-2 (BMP-2) in bone formation has been extensively characterized over the last 30 years [1,2]. The neuroscience field has also found significant involvement of BMPs in development, maturation, and repair of the peripheral nervous system (PNS) and central nervous system (CNS) [3–5]. Although the direct influence of the PNS on bone homeostasis is well described, the interactions through which peripheral neurons may influence bone formation or repair remain to be fully defined [6–8]. We would agree that further study of neuron-bone interaction could be highly significant for the orthopedic world. However, the potential role of BMPs in this interaction is largely unexplored. Neurogenic inflammation is a specific term that refers to inflammatory processes initiated by substances produced by neurons, such as calcitonin gene–related peptide (CGRP) or substance P. The work by Salisbury et al. [9,10] implicating neurogenic inflammation in development of heterotopic ossification is intriguing. Although this phenomenon can be induced by exogenous BMPs, it is unclear whether BMP-2 is critical to endogenous mechanisms regulating the heterotopic ossification formation after injury [10,11].
Letters to the Editor / The Spine Journal 11 (2011) 800–805
Adverse events and bone morphogenetic protein-2
To the Editor: Recently, a number of adverse events have been reported in the use of recombinant bone morphogenetic protein-2 (BMP-2) in spinal fusion [1–4]. We have been studying new bone formation after delivery of physiologic levels of BMP-2 using a cell therapy approach and have found this to rely on very selective neurogenic inflammation. We would like to suggest that this is actually a normal physiologic event in bone formation and fracture repair rather than an adverse event associated with delivery of this protein. First, our studies using BMP-2 have shown that neurogenic inflammation is one of the first steps necessary for bone formation [5,6]. Further, it appears that inhibition of this neuroinflammatory mechanism actually suppresses bone formation, further substantiating this connection. However, the exact mechanism remains uncertain. It may simply be that neurogenic inflammation is needed for innervation of the newly forming bone, most likely through axonal growth that requires nerve remodeling for sprouting. Alternatively, we have recently shown that peripheral nerves likely supply osteogenic cells [6]. Moreover, similar findings have been associated with fracture repair [7,8], where no exogenous BMPs are added. In these studies, peripheral nerves and release of neurogenic inflammatory mediators have been shown to play a critical role, with suppression of these factors blocking the bone healing [9]. Although both processes appear remarkably similar, it is unclear whether they are identical; however, this certainly raises the question of the role of the peripheral nervous system in bone formation and repair. Our data clearly suggest that nerve remodeling may be a normal physiologic process involved either directly or indirectly in new bone formation. Although more study is required to determine whether BMP-2 is launching an aberrant process or invoking this normal mechanism, the data clearly suggest that we should be careful in drawing conclusions prematurely. These facts drive home the point that a great deal more knowledge is needed on the mechanism of BMP-2 action in bone formation. It is now known that the brain is a central controller of bone homeostasis [10]. We suggest that it also controls bone repair but does so using the peripheral nervous system. We suggest that BMP-2 coordinates not only new bone formation and its ultimate fusion to preexisting skeletal bone in the event of fracture but also its innervation and vascular supply, without which it cannot be sustained.
References [1] Kang JD. Commentary: Another complication associated with rhBMP-2? Spine J 2011;11:517–9. [2] Smoljanovic T, Bojanic I. Commentary: An evolving perception of the risk of rhBMP-2 use for anterior spinal interbody fusions. Spine J 2011;11:520–1.
[3] Carragee EJ, Mitsunaga KA, Hurwitz EL, Scuderi GJ. Retrograde ejaculation after anterior lumbar interbody fusion using rhBMP-2: a cohort controlled study. Spine J 2011;11:511–6. [4] Dmitriev AE, Farhang S, Lehman RA Jr, et al. Bone morphogenetic protein-2 used in spinal fusion with spinal cord injury penetrates intrathecally and elicits a functional signaling cascade. Spine J 2010;10:16–25. [5] Salisbury E, Sonnet C, Heggeness M, et al. Heterotopic ossification has some nerve. Crit Rev Eukaryot Gene Expr 2010;20:313–24. [6] Salisbury E, Rodenberg E, Sonnet C, et al. Sensory nerve induced inflammation contributes to heterotopic ossification. J Cell Biochem 2011. [Epub ahead of print]. [7] Hukkanen M, Konttinen YT, Santavirta S, et al. Rapid proliferation of calcitonin gene-related peptide-immunoreactive nerves during healing of rat tibial fracture suggests neural involvement in bone growth and remodelling. Neuroscience 1993;54:969–79. [8] Li J, Kreicbergs A, Bergstrom J, et al. Site-specific CGRP innervation coincides with bone formation during fracture healing and modeling: a study in rat angulated tibia. J Orthop Res. 2007;25:1204–12. [9] Apel PJ, Crane D, Northam CN, et al. Effect of selective sensory denervation on fracture-healing: an experimental study of rats. J Bone Joint Surg Am 2009;91:2886–95. [10] Driessler F, Baldock PA. Hypothalamic regulation of bone. J Mol Endocrinol 2010;45:175–81.
Elizabeth A. Salisbury, BS Elizabeth A. Olmsted-Davis, PhD Alan R. Davis, PhD Houston, TX, USA FDA device/drug status: Not applicable. Author disclosures: EAS: Nothing to disclose. EAO-D: Nothing to disclose. ARD: Nothing to disclose. doi:10.1016/j.spinee.2011.07.017
Dmitriev et al. respond We appreciate the interest in our work by Salisbury et al. The role of bone morphogenetic protein-2 (BMP-2) in bone formation has been extensively characterized over the last 30 years [1,2]. The neuroscience field has also found significant involvement of BMPs in development, maturation, and repair of the peripheral nervous system (PNS) and central nervous system (CNS) [3–5]. Although the direct influence of the PNS on bone homeostasis is well described, the interactions through which peripheral neurons may influence bone formation or repair remain to be fully defined [6–8]. We would agree that further study of neuron-bone interaction could be highly significant for the orthopedic world. However, the potential role of BMPs in this interaction is largely unexplored. Neurogenic inflammation is a specific term that refers to inflammatory processes initiated by substances produced by neurons, such as calcitonin gene–related peptide (CGRP) or substance P. The work by Salisbury et al. [9,10] implicating neurogenic inflammation in development of heterotopic ossification is intriguing. Although this phenomenon can be induced by exogenous BMPs, it is unclear whether BMP-2 is critical to endogenous mechanisms regulating the heterotopic ossification formation after injury [10,11].