1. Bone Morphegenic Protein The Good, The Bad, and The
Interesting
2. The Good
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)
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
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
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.
Follow-up occurred at 6, 10, 14, 20, 26, 39, and 52 weeks.
Study Population: The study enrolled 450 patients with open
tibial fractures.
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.
3. The Good Cont.
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,
accelerating fracture and wound-healing, and reducing the
infection rate in
patients with an open fracture of the tibia.
4. The Bad
Report of Adverse Effects from Using rh-BMP-2 in Neck
Fusion
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.
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.
5. The Bad Cont.
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.
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.
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.
6. The Bad Cont.
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.
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.
Reference:
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.
7. The Interesting
BMP-7 blocks mesenchymal conversion of mesothelial cells and
prevents peritoneal damage induced by dialysis fluid exposure
Jess Loureiro1, Margot Schilte2, Abelardo Aguilera1, Patricia
Albar-Vizcano1, Marta Ramrez-Huesca1, M. Luisa Prez-Lozano1,
Guadalupe Gonzlez-Mateo3, Luiz S. Aroeira3, Rafael Selgas3, Lorea
Mendoza4, Alberto Ortiz5, Marta Ruz-Ortega5, Jacob van den Born2,
Robert H.J. Beelen2 and Manuel Lpez-Cabrera1,6 1 Unidad de Biologa
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
Investigacin and Servicio de Nefrologa, Hospital Universitario La
Paz, Madrid, Spain 4 Pharmakine SL, Derio, Vizcaya, Spain 5 Unidad
de Dilisis and Laboratorio de Investigacin Renal y Vascular,
Fundacin Jimnez Daz, Madrid, Spain 6 Centro de Biologa Molecular
Severo Ochoa, CSIC-UAM, Cantoblanco, Madrid, Spain, All the authors
from Spain belong to the Instituto Reina Sofa de Investigaciones
Nefrolgicas ,Manuel Lpez-Cabrera; E-mail: [email_address]
8. The Interesting Cont.
Abstract
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)-1, 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.
Methods. Epitheliod or non-epitheliod MC were analysed for the
expression of BMP-7, TGF-1, 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 MayGrnwaldGiemsa staining. Hyaluronic
acid levels were determined by ELISA.
9. The Interesting Cont.
Results. MC constitutively expressed BMP-7, and its expression
was downregulated during EMT. Treatment with recombinant BMP-7
resulted in blockade of TGF-1-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.
Conclusions. Data point to a balance between BMP-7 and TGF-1 in
the control of EMT and indicate that blockade of EMT may be a
therapeutic approach to ameliorate peritoneal membrane damage
during PD.
