transforming-growth-factor-beta and Spondylosis

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a single-gene disorder directly affecting the cerebral small blood vessels, that is caused by mutations in the HTRA1 gene encoding HtrA serine peptidase/protease 1 (HTRA1). CARASIL is the second known genetic form of ischemic, nonhypertensive, cerebral small-vessel diseases with an identified gene, following CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). The exact prevalence of CARASIL is currently unknown, and so far about 50 patients have been reported, most of them from Japan and two from China. Genetically no founder haplotype has been identified, and so the disease is expected to be found more widely. The main clinical manifestations are ischemic stroke or stepwise deterioration in brain functions, progressive dementia, premature baldness, and attacks of severe low back pain or spondylosis deformans/disk herniation. The most characteristic brain MRI findings are homogeneously confluent white-matter changes and multiple lacunar infarctions in the basal ganglia and thalamus. Histopathologically, CARASIL is characterized by intense arteriosclerosis, mainly in the small penetrating arteries, without granular osmiophilic materials (GOM) or amyloid deposition. CARASIL is a prototype single-gene disorder of cerebral small vessels, secondary to and distinct from CADASIL. CARASIL-associated mutant HTRA1s exhibited decreased protease activity and failed to repress transforming growth factor-β (TGF-β) family signaling, indicating that the increased TGF-β signaling causes arteriopathy in CARASIL. Therefore, HTRA1 represents another new gene to be considered in future studies of the mechanisms and therapeutic strategies of cerebral small-vessel diseases, as well as alopecia and degenerative vertebral/disk diseases.

Topics: Adult; Alopecia; Blood Vessels; Brain; Cerebral Infarction; Dementia, Vascular; Genes, Recessive; High-Temperature Requirement A Serine Peptidase 1; Humans; Leukoencephalopathy, Progressive Multifocal; Low Back Pain; Male; Middle Aged; Mutation; Serine Endopeptidases; Spondylosis; Syndrome; Transforming Growth Factor beta

Review of literature.. To evaluate the available literature supporting the use of lumbar fusion extenders in clinical practice.. Because of the morbidity associated with the harvest of autologous iliac crest bone grafts, the search for lumber fusion extenders and replacements has accelerated. Many formulations of lumbar fusion extenders have been developed, and it is essential to evaluate clinical literature and available outcome metrics of these extenders.. A review of English-language literature was performed between 1990 and January of 2010 for all literature presenting clinical outcomes of lumbar fusion extenders. After controlling for inclusion and exclusion criteria and assigning levels of evidence, 19 clinical studies were fully reviewed including those for demineralized bone matrix, recombinant human bone morphogenetic protein 2 (rhBMP-2), β-tricalcium phosphate, and calcium sulfate.. The most extensively studied of the lumbar fusion extenders is β-tricalcium phosphate, especially with regard to its use in adolescent scoliosis correction. The use of rhBMP-2 and demineralized bone matrix is supported only by two and three clinical studies, respectively. Calcium sulfate and other miscellaneous extenders are not conclusively or consistently supported by available clinical studies.. Calcium phosphate is the most supported of the lumbar fusion extenders. rhBMP-2 and demineralized bone matrix are supported by smaller bodies of evidence. These formulations are supported by these initial studies but in some cases need to be better examined with regard to side effect profiles.

Topics: Bone Morphogenetic Protein 2; Bone Substitutes; Bone Transplantation; Calcium Phosphates; Humans; Intervertebral Disc Degeneration; Lumbar Vertebrae; Recombinant Proteins; Spinal Fusion; Spondylosis; Transforming Growth Factor beta

This study evaluated the safety of 3-level anterior cervical diskectomy and fusion (ACDF) with ultra-low-dose recombinant bone morphogenetic protein-2 (rhBMP-2). Thirty-seven consecutive patients with cervical spondylotic myelopathy who were treated with 3-level ACDF and rhBMP-2 were evaluated. Complications such as airway or cervical swelling or hematoma were not observed. The rate of dysphagia was no different at 1, 2, and 6 months postoperatively compared with reports in the literature without rhBMP-2. There were significant improvements in VAS neck/arm pain, Oswestry Neck Disability Index, and cervical lordosis. The use of ultra-low-dose rhBMP-2 for 3-level ACDF may be efficacious for surgically addressing 3-level spondylotic myelopathy.

Topics: Adult; Aged; Bone Morphogenetic Protein 2; Diskectomy; Female; Humans; Male; Middle Aged; Recombinant Proteins; Retrospective Studies; Spinal Fusion; Spondylosis; Transforming Growth Factor beta; Treatment Outcome

Twenty-four consecutive patients with cervical spondylosis who were treated with cervical corpectomy and recombinant human bone morphogenetic protein-2 (rhBMP-2) with standalone anterior instrumentation were evaluated. Mean number of levels fused was 2.4. There were significant improvements in visual analog scale neck pain and Oswestry Disability Index scores and cervical lordosis. Cervical corpectomy with a lower dose of rhBMP-2 was found to be safe and efficacious for patients who are at a higher risk for pseudarthrosis.

Topics: Aged; Bone Morphogenetic Protein 2; Cervical Vertebrae; Female; Humans; Male; Middle Aged; Pseudarthrosis; Recombinant Proteins; Spinal Fusion; Spondylosis; Transforming Growth Factor beta

Retrograde ejaculation (RE) is a complication of anterior lumbar interbody fusion (ALIF) techniques. Most commonly, this results from mechanical or inflammatory injury to the superior hypogastric plexus near the aortic bifurcation. Bone morphogenetic protein-2 (BMP-2) has been used in spinal fusions and has been associated with inflammatory and neuroinflammatory adverse reactions, which may contribute to RE development after anterior lumbar surgery.. While controlling for anterior approach technique, we compared the incidence of RE with and without rhBMP-2 exposure, in large, matched cohorts of patients after ALIF.. Retrospective analysis of 10 years of prospectively gathered outcomes data on consecutive-patient cohorts having the same anterior exposure technique for ALIF with and without rhBMP-2 use.. All male patients without baseline sexual incapacity and having ALIF for lumbar spondylosis or spondylolisthesis of the lowest one or two lumbar levels with and without rhBMP-2, from 2002 through 2011.. Diagnosis of RE as a new finding after ALIF compared against BMP-2 exposure, comorbid conditions, and other urological complications after ALIF surgery.. From the comprehensive surgical database at a high volume, university practice, male subjects having ALIF at one (L5/S1) or two levels (L4/5, L5/S1) from 2002 to 2011 were identified. Baseline comorbid factors, postoperative urinary catheter/retention events, and RE events were recorded and comparative incidence compared.. There were four consecutive-patient cohorts identified: one before rhBMP-2 use was adopted (n=174), two cohorts in which BMP-2 use was routine (n=88 and n=151), and one final cohort after BMP-2 use was discontinued from routine use (n=59). The cohorts with and without BMP-2 exposure were closely comparable for age, approach, levels of surgery, comorbid factors affecting RE. Of 239 patients with ALIF and exposure to BMP-2, RE was diagnosed in 15 subjects (6.3%), compared with an RE diagnosis rate of two of 233 control patients without BMP-2 exposure (0.9%; p=.0012). Urinary retention after bladder catheter removal was also more frequently observed in patients exposed to BMP-2 (9.7%) compared with control patients (4.6%; p=.043). Of the baseline comorbid factors, medical or surgical treatment for prostatic hypertrophy disease was associated with an increased risk of RE in the BMP-2 patients (p=.034).. This study confirms previous reports of a higher rate of RE in ALIF procedures using rhBMP-2 and an open anterior approach to the spine. This effect may be associated with an increased risk of postoperative urinary retention after BMP-2 exposure. The magnitude of the RE effect may be increased with concomitant prostatic disease treatments.

Topics: Adult; Aged; Bone Morphogenetic Protein 2; Ejaculation; Humans; Lumbar Vertebrae; Male; Middle Aged; Postoperative Complications; Recombinant Proteins; Retrospective Studies; Sexual Dysfunction, Physiological; Spinal Fusion; Spondylolisthesis; Spondylosis; Transforming Growth Factor beta; Young Adult

Case report.. Two cases are presented in which the use of recombinant bone morphogenetic protein-2 (rh-BMP-2) in a posterior cervical decompression and instrumented arthrodesis may have contributed to seroma formation and cord compression.. The use of rh-BMP-2 has been proven effective in promoting bone formation in anterior lumbar spine arthrodesis. Whether rh-BMP-2 is safe and/or effective in the cervical spine has not been determined. Adverse effects when it is used for anterior cervical fusion procedures have been reported but its role in posterior cervical decompression and instrumented fusions has yet to be determined.. We report on two cases. The first is a 68-year-old man presenting with a substantial decline in his neurologic status approximately 2 weeks after surgery. The second is a 44-year-old man presenting with a substantial decline in his neurologic status approximately 5 days after surgery. Both complications occurred after a posterior cervical laminectomy and instrumented arthrodesis when rh-BMP-2 was used as a bone graft substitute.. Both patients were found to have a moderate-to-large seroma causing severe compression on the spinal cord and were urgently taken to an operating room for evacuation of the seromas. Both showed improvement of their neurologic status immediately after surgery. As rh-BMP-2 is known to occasionally cause seroma formation it is postulated that it may have been the cause of the seromas.. Caution should be exercised with rh-BMP-2 use in posterior cervical applications when a laminectomy has been performed. The safe and effective dose and technique for application have yet to be determined. Seroma formation is possible, which can cause acute stenosis with cord compression and neurologic compromise.

Topics: Adult; Aged; Arthrodesis; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Cervical Vertebrae; Decompression, Surgical; Humans; Male; Postoperative Complications; Recombinant Proteins; Seroma; Spinal Cord Compression; Spinal Stenosis; Spondylosis; Tomography, X-Ray Computed; Transforming Growth Factor beta; Treatment Outcome

The commercially available growth factor recombinant bone morphogenic protein-2 (rhBMP-2) used in spinal fusion has been associated with numerous adverse reactions, including inflammatory reactions in soft tissue, heterotopic bone formation, radiculitis, osteolysis, and cage or graft subsidence. The original Food and Drug Administration Summary of anterior lumbar interbody fusion (ALIF) reported 12 retrograde ejaculation (RE) events (8%) in the rhBMP-2 groups compared with (1.4%) in the control group. It had been debated whether this finding was related to rhBMP-2 use.. To compare the incidence of RE after ALIF in patients with and without rhBMP-2 use.. Retrospective analysis of prospectively gathered outcomes data on consecutive subjects having ALIF with and without rhBMP-2 use.. Male patients with lumbar spondylosis or spondylolisthesis having ALIF of the lowest one or two lumbar levels with and without rhBMP-2.. Report of RE as a new finding after ALIF.. From the comprehensive outcome database at a high-volume university practice, male subjects having ALIF for one- (L5/S1) or two-level (L4/L5, L5/S1) lumbar fusion were identified. Retrograde ejaculation events were recorded and comparative incidence compared.. The two groups were comparable for age and additional procedures performed. There were 69 L5/S1 ALIFs performed with rhBMP-2 and 174 ALIFs performed without rhBMP-2 during the study period. Of those, 24 and 64 were two-level ALIFs performed with and without rhBMP-2, respectively. There were five RE events (7.2%) reported in the rhBMP-2 group and 1 (0.6%) in the control group. Comparing single-level L5/S1 ALIF, there was a 6.7% and 0% rate of RE in the rhBMP-2 versus control groups, respectively. At 1 year after surgery, three of six affected subjects reported resolution of the RE.. This study confirms previous reports of a higher rate of RE in ALIF procedures using rhBMP-2. This may be an important consideration in subjects concerned with sterility after surgery.

Topics: Adult; Aged; Bone Morphogenetic Protein 2; Cohort Studies; Ejaculation; Humans; Lumbar Vertebrae; Male; Middle Aged; Postoperative Complications; Recombinant Proteins; Retrospective Studies; Sexual Dysfunction, Physiological; Spinal Fusion; Spondylosis; Transforming Growth Factor beta; Young Adult

The genetic cause of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), which is characterized by ischemic, nonhypertensive, cerebral small-vessel disease with associated alopecia and spondylosis, is unclear.. In five families with CARASIL, we carried out linkage analysis, fine mapping of the region implicated in the disease, and sequence analysis of a candidate gene. We also conducted functional analysis of wild-type and mutant gene products and measured the signaling by members of the transforming growth factor beta (TGF-beta) family and gene and protein expression in the small arteries in the cerebrum of two patients with CARASIL.. We found linkage of the disease to the 2.4-Mb region on chromosome 10q, which contains the HtrA serine protease 1 (HTRA1) gene. HTRA1 is a serine protease that represses signaling by TGF-beta family members. Sequence analysis revealed two nonsense mutations and two missense mutations in HTRA1. The missense mutations and one of the nonsense mutations resulted in protein products that had comparatively low levels of protease activity and did not repress signaling by the TGF-beta family. The other nonsense mutation resulted in the loss of HTRA1 protein by nonsense-mediated decay of messenger RNA. Immunohistochemical analysis of the cerebral small arteries in affected persons showed increased expression of the extra domain-A region of fibronectin and versican in the thickened tunica intima and of TGF-beta1 in the tunica media.. CARASIL is associated with mutations in the HTRA1 gene. Our findings indicate a link between repressed inhibition of signaling by the TGF-beta family and ischemic cerebral small-vessel disease, alopecia, and spondylosis.

Topics: Adult; Aged, 80 and over; Alopecia; Cerebral Arterial Diseases; Cerebral Arteries; Cerebral Infarction; Female; Genes, Recessive; High-Temperature Requirement A Serine Peptidase 1; Humans; Male; Middle Aged; Mutation; Pedigree; Serine Endopeptidases; Signal Transduction; Spondylosis; Syndrome; Transcription, Genetic; Transforming Growth Factor beta; Tunica Intima