Browsing by Subject "Bone Morphogenetic Proteins"

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    BMP signaling in the development of the mouse esophagus and forestomach.
    (Development, 2010-12) Rodriguez, Pavel; Da Silva, Susana; Oxburgh, Leif; Wang, Fan; Hogan, Brigid LM; Que, Jianwen
    The stratification and differentiation of the epidermis are known to involve the precise control of multiple signaling pathways. By contrast, little is known about the development of the mouse esophagus and forestomach, which are composed of a stratified squamous epithelium. Based on prior work in the skin, we hypothesized that bone morphogenetic protein (BMP) signaling is a central player. To test this hypothesis, we first used a BMP reporter mouse line harboring a BRE-lacZ allele, along with in situ hybridization to localize transcripts for BMP signaling components, including various antagonists. We then exploited a Shh-Cre allele that drives recombination in the embryonic foregut epithelium to generate gain- or loss-of-function models for the Bmpr1a (Alk3) receptor. In gain-of-function (Shh-Cre;Rosa26(CAG-loxpstoploxp-caBmprIa)) embryos, high levels of ectopic BMP signaling stall the transition from simple columnar to multilayered undifferentiated epithelium in the esophagus and forestomach. In loss-of-function experiments, conditional deletion of the BMP receptor in Shh-Cre;Bmpr1a(flox/flox) embryos allows the formation of a multilayered squamous epithelium but this fails to differentiate, as shown by the absence of expression of the suprabasal markers loricrin and involucrin. Together, these findings suggest multiple roles for BMP signaling in the developing esophagus and forestomach.
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    Bone morphogenetic protein 10: a novel risk marker of ischaemic stroke in patients with atrial fibrillation.
    (European heart journal, 2023-01) Hijazi, Ziad; Benz, Alexander P; Lindbäck, Johan; Alexander, John H; Connolly, Stuart J; Eikelboom, John W; Granger, Christopher B; Kastner, Peter; Lopes, Renato D; Ziegler, André; Oldgren, Jonas; Siegbahn, Agneta; Wallentin, Lars

    Aims

    Biomarkers specifically related to atrial tissue may increase the understanding of the pathophysiology of atrial fibrillation (AF) and further improve risk prediction in this setting. Bone morphogenetic protein 10 (BMP10) is a protein expressed in the atrial myocardium. We evaluated the association between BMP10 and the risk of ischaemic stroke and other cardiovascular events in large cohorts of patients with AF, treated with and without oral anticoagulation (OAC).

    Methods and results

    BMP10 was measured in plasma samples collected at randomisation in patients with AF without OAC in the ACTIVE A and AVERROES trials (n = 2974), and with OAC in the ARISTOTLE trial (n = 13 079). BMP10 was analysed with a prototype Elecsys immunoassay. Associations with outcomes were evaluated by Cox-regression models adjusted for clinical characteristics, kidney function, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Median concentrations of BMP10 were 2.47 and 2.44 ng/mL, in the non-OAC and OAC cohort, respectively. Increasing BMP10 was associated with lower body mass index, older age, female sex, kidney dysfunction, and AF rhythm. BMP10 was consistently associated with ischaemic stroke. In the non-OAC cohort, BMP10 increased the concordance index of the multivariable model from 0.713 to 0.733 (P = 0.004) and in the OAC cohort from 0.673 to 0.694 (P < 0.001). Additionally, BMP10 maintained a significant prognostic value after additionally adjusting for NT-proBNP. BMP10 was not independently associated with bleeding or with death.

    Conclusion

    The novel atrial biomarker BMP10 was independently associated with ischaemic stroke in patients with AF irrespective of OAC treatment. BMP10 seems to be more specifically related to the risk of ischaemic stroke in AF.

    One-sentence summary

    In this study, BMP10 may be a novel specific biomarker of ischaemic stroke in patients with atrial fibrillation, irrespective of oral anticoagulation.
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    Complications, revision fusions, readmissions, and utilization over a 1-year period after bone morphogenetic protein use during primary cervical spine fusions.
    (The spine journal : official journal of the North American Spine Society, 2014-09) Goode, Adam P; Richardson, William J; Schectman, Robin M; Carey, Timothy S

    Background context

    Nationwide estimates examining bone morphogenetic protein (BMP) use with cervical spine fusions have been limited to perioperative outcomes.

    Purpose

    To determine the 1-year risk of complications, cervical revision fusions, hospital readmissions, and health care services utilization.

    Study design

    A retrospective cohort study from 2002 to 2009 using a nationwide claims database.

    Patient sample

    There were 61,937 primary cervical spine fusions of which 1,677 received BMP.

    Outcome measures

    Complications, revision fusions, 30-day hospital readmission, and health care utilization.

    Methods

    Data for these analyses come from the Thomson Reuters MarketScan Commercial Claims and Encounters Database 2010. Patients were aged 18 to 64 years, receiving and not receiving BMP with a primary (C2-C7) cervical spine fusion. All outcomes were defined by International Classification of Diseases, 9th edition Clinical Modification and Current Procedural and Terminology, 4th edition codes. Complications were analyzed as any complication and stratified by nervous system, wound, and dysphagia or hoarseness. Cervical revision fusions were determined in the 1-year follow-up. Hospital readmission discharge records defined 30-day hospital readmission and reason for the readmission. The utilization of at least one health care service of cervical spine imaging, epidural usage or rehabilitation service was examined. Poisson regression models were used to estimate the relative risk and 95% confidence interval (CI). Linear regression was used to determine the time to hospital readmission. Results were stratified by anterior or posterior and circumferential approaches.

    Results

    Patients receiving BMP were 29% more likely to have a complication (adjusted relative risk [aRR]=1.29 [95% CI, 1.14-1.46]) and a nervous system complication (aRR=1.42 [95% CI, 1.10-1.83]). Cervical revision fusions were more likely among patients receiving BMP (aRR=1.69 [95% CI, 1.35-2.13]). The risk of 30-day readmission was greater with BMP use (aRR=1.37 [95% CI, 1.07-1.73]) and readmission occurred 27.4% sooner on an average. Patients receiving BMP were more likely to receive computed tomography scans (aRR=1.34 [95% CI, 1.06-1.70]) and epidurals with anterior surgical approaches (aRR=1.29 [95% CI, 1.00-1.65]).

    Conclusions

    These findings question both the safety and effectiveness of off-label BMP use in primary cervical spine fusions.
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    Does bone morphogenetic protein increase the incidence of perioperative complications in spinal fusion? A comparison of 55,862 cases of spinal fusion with and without bone morphogenetic protein.
    (Spine, 2011-09) Williams, Brian J; Smith, Justin S; Fu, Kai-Ming G; Hamilton, D Kojo; Polly, David W; Ames, Christopher P; Berven, Sigurd H; Perra, Joseph H; Knapp, Dennis R; McCarthy, Richard E; Shaffrey, Christopher I; Scoliosis Research Society Morbidity and Mortality Committee

    Study design

    Retrospective review of a multi-institutional, multisurgeon database.

    Objective

    Assess for associations between bone morphogenetic protein (BMP) use and rate of complications in spinal fusion.

    Summary of background data

    BMP is commonly used in spinal surgery to augment fusion; however, there is limited evidence demonstrating its associated complications.

    Methods

    We performed a retrospective analysis of all fusion cases submitted by members of the Scoliosis Research Society from 2004 to 2007. We stratified on the basis of the use of BMP and evaluated for complications and associated characteristics.

    Results

    A total of 55,862 cases of spinal fusion were identified with BMP used in 21% (11,933) of the cases. Excluding anterior cervical fusions, there were no significant differences between fusions with and without BMP with regard to overall complications (8.4% vs. 8.5%; P = 0.5), wound infections (2.4% vs. 2.4%; P = 0.8), or epidural hematomas/seromas (0.2% vs. 0.2%; P = 0.3). Anterior cervical fusions with BMP were associated with more overall complications (5.8% vs. 2.4%; P < 0.001) and more wound infections (2.1% vs. 0.4%; P < 0.001) than fusions without BMP. On multivariate analysis for thoracolumbar and posterior cervical fusions, BMP use was not a significant predictor of complications (P = 0.334; odds ratio = 1.039; 95% confidence interval = 0.961-1.124; covariates were BMP use, patient age, revision vs. primary surgery). Multivariate analysis for anterior cervical spinal fusion demonstrated that BMP use remained a significant predictor of complications (P < 0.001, odds ratio = 1.6; 95% confidence interval = 1.516-1.721), after adjusting for the effects of patient age and whether the surgery was a revision procedure.

    Conclusion

    BMP use with anterior cervical fusion was associated with an increased incidence of complications. Use of BMP was not associated with more complications in thoracolumbar and posterior cervical fusions.
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    Long-Segment Fusion for Adult Spinal Deformity Correction Using Low-Dose Recombinant Human Bone Morphogenetic Protein-2: A Retrospective Review of Fusion Rates.
    (Neurosurgery, 2016-08) Schmitt, Paul J; Kelleher, John P; Ailon, Tamir; Heller, Joshua E; Kasliwal, Manish K; Shaffrey, Christopher I; Smith, Justin S

    Background

    Although use of very high-dose recombinant human bone morphogenetic protein-2 (rhBMP-2) has been reported to markedly improve fusion rates in adult spinal deformity (ASD) surgery, most centers use much lower doses due to cost constraints. How effective these lower doses are for fusion enhancement remains unclear.

    Objective

    To assess fusion rates using relatively low-dose rhBMP-2 for ASD surgery.

    Methods

    This was a retrospective review of consecutive ASD patients that underwent thoracic to sacral fusion. Patients that achieved 2-year follow-up were analyzed. Impact of patient and surgical factors on fusion rate was assessed, and fusion rates were compared with historical cohorts.

    Results

    Of 219 patients, 172 (78.5%) achieved 2-year follow-up and were analyzed. Using an average rhBMP-2 dose of 3.1 mg/level (average total dose = 35.9 mg/case), the 2-year fusion rate was 73.8%. Cancellous allograft, local autograft, and very limited iliac crest bone graft (<20 mL, obtained during iliac bolt placement) were also used. On multivariate analysis, female sex was associated with a higher fusion rate, whereas age, comorbidity score, deformity type, and 3-column osteotomy were not. There were no complications directly attributable to rhBMP-2.

    Conclusion

    Fusion rates for ASD using low-dose rhBMP-2 were comparable to those reported for iliac crest bone graft but lower than for high-dose rhBMP-2. Importantly, there were substantial differences between patients in the present series and those in the historical comparison groups that could not be fully adjusted for based on available data. Prospective evaluation of rhBMP-2 dosing for ASD surgery is warranted to define the most appropriate dose that balances benefits, risks, and costs.

    Abbreviations

    ASD, adult spinal deformityICBG, iliac crest bone graftOR, odds ratiorhBMP-2, recombinant human bone morphogenetic protein-2RR, risk ratioTCO, 3-column osteotomy.
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    Multiple-day drainage when using bone morphogenic protein for long-segment thoracolumbar fusions is associated with low rates of wound complications.
    (World neurosurgery, 2013-07) Saulle, Dwight; Fu, Kai-Ming G; Shaffrey, Christopher I; Smith, Justin S

    Background

    Concerns over increased wound complication rates have been raised when bone morphogenic protein (BMP) is used as an adjunct for fusion in spinal surgery. This study evaluated 87 consecutive patients undergoing long-segment thoracolumbar spinal fusions with BMP to assess drain output and the rates of reoperation for infection or seroma.

    Methods

    Inclusion criteria included patients undergoing 4 or more levels of posterior instrumented thoracolumbar fusion, use of BMP, age >18 years, and a perioperative follow-up of ≥60 days. Drain output, length of time of drainage, and need for reoperation for wound seroma or infection were reviewed.

    Results

    A total of 87 patients met inclusion criteria and had a mean age of 58.5 years (SD 16, range 20 to 81). The average number of levels instrumented and arthrodesed with BMP was 9.2 (SD 3.7; range 4 to 18), and the average dose of BMP used was 31.2 mg (SD 9.6, range 12 to 48) or 2.6 large sponges. Patients required drainage for a mean of 4.9 days (SD 1.3, range 3 to 9). The average total output was 1923 mL (SD 865, range 530 to 4310 mL). The wound infection rate was 2.3% (2 cases of deep wound infection that required reoperation). There was one (1.1%) hematoma, and one (1.1%) sterile seroma, both requiring evacuation. No other wound complications were noted.

    Conclusions

    Use of BMP for long-segment posterior thoracolumbar fusions may be associated with significant drain output, requiring multiple days of drainage. However, when drained adequately, infections and seromas occur infrequently.