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Bone Morphegenic Protein


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Bone Morphegenic Protein

  1. 1. Bone Morphegenic Protein The Good, The Bad, and The Interesting
  2. 2. The Good <ul><li>c. Govender conducted a study to determine whether rhBMP-2 on an absorbable type I collagen sponge resulted in an increased rate of fracture-healing as evidenced by a reduction in the number of secondary interventions and by clinical and radiographic assessments. (Govender 2002) </li></ul><ul><li>The prospective, randomized controlled, single-blind study was conducted at 49 centers in 11 countries. Based on the Gustilo-Anderson classification of open wounds, patients were randomized to: 1. control - standard of care only (intramedullary nail fixation and routine soft tissue management) 2. standard of care and implant containing .75 mg/ml of rhBMP-2 3. standard of care and implant containing 1.50 mg/ml of rhBMP-2 </li></ul><ul><li>The primary study efficacy end point was proportion of patients who received secondary interventions within 12 months after definitive wound closure. Researchers defined a healed fracture as fulfillment of clinical criteria, including full weight-bearing and lack of tenderness at the fracture site on palpation, as well as radiographic evidence of fracture union. Two of 3 blinded, independent radiologists must have reported cortical bridging and/or disappearance of the fracture lines on at least 3 of 4 cortices viewed on anteroposterior and lateral </li></ul><ul><li>radiographs. Treatment failure was defined as a recommendation for a secondary intervention. Researcher assessed safety via adverse event monitoring. They also measured patient antibody response to rhBMP-2 and bovine Type I collagen by serum sampling at baseline, 6 weeks, and 20 weeks. </li></ul><ul><li>Follow-up occurred at 6, 10, 14, 20, 26, 39, and 52 weeks. </li></ul><ul><li>Study Population: The study enrolled 450 patients with open tibial fractures. </li></ul><ul><li>Definitive fracture fixation with intramedullary nailing was performed no laterthan 14 days after injury. The median time from injury to wound closure was 3 days. </li></ul>
  3. 3. The Good Cont. <ul><li>Conclusion: rhBMP-2 implant was safe and, when 1.50 mg/ml was used,significantly superior to the standard of care in reducing the frequency of secondary interventions and the overall invasiveness of the procedures, </li></ul><ul><li>accelerating fracture and wound-healing, and reducing the infection rate in </li></ul><ul><li>patients with an open fracture of the tibia. </li></ul>
  4. 4. The Bad <ul><li>Report of Adverse Effects from Using rh-BMP-2 in Neck Fusion </li></ul><ul><li>rh-BMP-2 (BMP) is a protein that helps bone heal. It has been used with good results in spinal fusion of the lumbar spine. BMP helps speed up the recovery rate after lumbar spinal fusion. It has not been approved by the FDA yet for use in the cervical (neck) spine. </li></ul><ul><li>Doctors at the Institute for Spinal Disorders in Los Angeles report on the case of one patient who had a bad reaction to BMP. A 54-year old man had an anterior cervical discectomy and fusion (ACDF). Several discs were removed and a metal plate attached to fuse the neck. </li></ul>
  5. 5. The Bad Cont. <ul><li>A bioresorbable implant called a cage was put in place of the disc to help hold the vertebrae until healing took place. Bone graft containing BMP was put inside the cage to stimulate bone growth and help speed up fusion. </li></ul><ul><li>Three days later, the patient started having neck swelling and trouble swallowing. On day five after surgery, he arrived at the emergency room with massive neck swelling. Neurologic signs were normal. The patient was able to breathe okay. Lab values were all normal. </li></ul><ul><li>MRIs showed the trachea was pushed over to the side and flattened by severe soft-tissue swelling. Several pockets of air (gas) could be seen on a CT scan. The gas appeared to be inside the track of fluid (swelling). The patient was treated in the ICU for three days and stabilized enough to go home again. </li></ul>
  6. 6. The Bad Cont. <ul><li>This is the first report describing an adverse response to rh-BMP-2 when used in the cervical spine. The authors suggest that the sponge used to hold the BMP may have released too much of the protein too fast. </li></ul><ul><li>BMP is designed to promote bone formation by setting up an inflammatory reaction. It's likely that reducing the amount of BMP used could tone down the inflammatory response and avoid the swelling seen in this case. This report is meant to alert other surgeons of the possible dose/carrier problems with BMP. </li></ul><ul><li>Reference:  </li></ul><ul><li>Brian Perri, DO, et al. Adverse Swelling Associated with Use of rh-BMP-2 in Anterior Cervical Discectomy and Fusion: A Case Study. In The Spine Journal. March 2007. Vol. 7. No. 2. Pp. 235-239. </li></ul>
  7. 7. The Interesting <ul><li>BMP-7 blocks mesenchymal conversion of mesothelial cells and prevents peritoneal damage induced by dialysis fluid exposure </li></ul><ul><li>Jesús Loureiro1, Margot Schilte2, Abelardo Aguilera1, Patricia Albar-Vizcaíno1, Marta Ramírez-Huesca1, M. Luisa Pérez-Lozano1, Guadalupe González-Mateo3, Luiz S. Aroeira3, Rafael Selgas3, Lorea Mendoza4, Alberto Ortiz5, Marta Ruíz-Ortega5, Jacob van den Born2, Robert H.J. Beelen2 and Manuel López-Cabrera1,6 1 Unidad de Biología Molecular, Hospital Universitario de la Princesa, Madrid, Spain 2 Departments of Molecular Cell Biology & Immunology, VU University Medical Centre, Amsterdam, The Netherlands 3 Unidad de Investigación and Servicio de Nefrología, Hospital Universitario La Paz, Madrid, Spain 4 Pharmakine SL, Derio, Vizcaya, Spain 5 Unidad de Diálisis and Laboratorio de Investigación Renal y Vascular, Fundación Jiménez Díaz, Madrid, Spain 6 Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Cantoblanco, Madrid, Spain, All the authors from Spain belong to the Instituto Reina Sofía de Investigaciones Nefrológicas ,Manuel López-Cabrera; E-mail: [email_address] </li></ul>
  8. 8. The Interesting Cont. <ul><li>   Abstract </li></ul><ul><li>Background. During peritoneal dialysis (PD), mesothelial cells (MC) undergo an epithelial-to-mesenchymal transition (EMT), and this process is associated with peritoneal membrane (PM) damage. Bone morphogenic protein-7 (BMP-7) antagonizes transforming growth factor (TGF)-β1, modulates EMT and protects against fibrosis. Herein, we analysed the modulating role of BMP-7 on EMT of MC in vitro and its protective effects in a rat PD model. </li></ul><ul><li>Methods. Epitheliod or non-epitheliod MC were analysed for the expression of BMP-7, TGF-β1, activated Smads, epithelial cadherin (E-cadherin), collagen I, alpha smooth muscle cell actin ( -SMA) and vascular endothelial growth factor (VEGF) using standard procedures. Rats were daily instilled with PD fluid with or without BMP-7 during 5 weeks. Histological analyses were carried out in parietal peritoneum. Fibrosis was quantified with van Gieson or Masson's trichrome staining. Vasculature, activated macrophages and invading MC were quantified by immunofluorescence analysis. Quantification of infiltrating leukocytes and MC density in liver imprints was performed by May–Grünwald–Giemsa staining. Hyaluronic acid levels were determined by ELISA. </li></ul>
  9. 9. The Interesting Cont. <ul><li>Results. MC constitutively expressed BMP-7, and its expression was downregulated during EMT. Treatment with recombinant BMP-7 resulted in blockade of TGF-β1-induced EMT of MC. We provide evidence of a Smad-dependent mechanism for the blockade of EMT. Exposure of rat peritoneum to PD fluid resulted in inflammatory and regenerative responses, invasion of the compact zone by MC, fibrosis and angiogenesis. Administration of BMP-7 decreased the number of invading MC and reduced fibrosis and angiogenesis. In contrast, BMP-7 had no effect on inflammatory and regenerative responses, suggesting that these are EMT-independent, and probably upstream, processes. </li></ul><ul><li>Conclusions. Data point to a balance between BMP-7 and TGF-β1 in the control of EMT and indicate that blockade of EMT may be a therapeutic approach to ameliorate peritoneal membrane damage during PD. </li></ul><ul><li>Keywords: bone morphogenic protein-7; epithelial-to-mesenchymal transition; fibrosis; peritoneal dialysis; transforming growth factor-β1 </li></ul><ul><li>Received for publication: 5. 6.09 Revision received 23.10.09. </li></ul>