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Biomedical subjects

Jay R Lieberman

Publications and source records attributed to Jay R Lieberman.

At least 19 recordsLinked to original sources
PubMed2005

Overexpression of noggin inhibits BMP-mediated growth of osteolytic prostate cancer lesions.

INTRODUCTION: Although a majority of metastatic prostate cancer lesions are osteoblastic in nature, some are mixed or lytic; and, osteoblastic lesions require osteolytic activity in order to progress. The role of BMPs in the formation of prostate cancer metastases to bone remains unknown. We hypothesized that BMPs influence the development and progression of osteolytic prostate cancer lesions. METHODS: RT-PCR and Western blot analysis were used to determine BMP receptor expression on the osteolytic prostate cancer cell line PC-3. Migration, invasion, and cellular proliferation assays were performed on PC-3 cells to quantify the effects of BMP-2, -4, and -7. In vivo, PC-3 cells were injected alone, with an empty retroviral vector, or with a retroviral vector overexpressing noggin, into the tibias of SCID mice. The animals were followed for 8 weeks, and histologic and radiographic analysis were performed at 2, 4, 6, and 8 weeks. RESULTS: BMP receptors are expressed on PC-3 cells, suggesting that they would be responsive to host BMP secretion. BMP-2, and to a lesser extent, BMP-4, stimulated PC-3 cell migration and invasion in a dose-dependent fashion. Noggin inhibited cellular migration and invasion of BMP-2 and -4 stimulated PC-3 cells. BMP-2 alone stimulated PC-3 cell proliferation, but BMP-4 had no effect. BMP-7 had no effect on proliferation, migration, or invasion. PC-3 cells implanted into SCID mouse tibias formed osteolytic lesions as early as 2 weeks and completely destroyed the proximal tibia by 8 weeks. Overexpression of noggin in PC-3 cells inhibited the expansion of the lesion in vivo. CONCLUSIONS: BMPs influence the formation of the osteolytic prostate cancer metastases, and treatment modalities that inhibit BMP activity may limit the progression of the lytic component of prostate cancer metastases.

Animals↗
PubMed2005

The effects of RANK blockade and osteoclast depletion in a model of pure osteoblastic prostate cancer metastasis in bone.

Adenocarcinoma of the prostate exhibits a clear propensity for bone and is associated with the formation of osteoblastic metastases. It has previously been suggested that osteoclast activity may be necessary for the development of these osteoblastic metastases based on data from lytic and mixed lytic-blastic tumors. Here we investigate the effects of complete in vivo osteoclast depletion via the blockade of receptor activator of NF:kappaB (RANK) on the establishment and progression of purely osteoblastic (LAPC-9 cells) bone lesions induced by human prostate cancer cells using a SCID mouse intratibial injection model. The subcutaneous administration of the RANK antagonist (15 mg/kg) RANK:Fc did not prevent the formation of purely osteoblastic lesions, indicating that osteoclasts may not be essential to the initial development of osteoblastic metastases. However, RANK:Fc protein appeared to inhibit the progression of established osteoblastic lesions, suggesting that osteoclasts may be involved in the subsequent growth of these tumors once they are already present. In contrast, RANK:Fc treatment effectively blocked the establishment and progression of purely osteolytic lesions formed by PC-3 cells, which served as a positive control. These results indicate that in vivo RANK blockade may not be effective for the prevention of osteoblastic metastasis but may potentially represent a novel therapy that limits the growth of established metastatic CaP lesions in bone.

Animals↗
PubMed2005

Genetically modified human derived bone marrow cells for posterolateral lumbar spine fusion in athymic rats: beyond conventional autologous bone grafting.

STUDY DESIGN: This experimental study consisted of four groups. In Group I, 8 animals were implanted with a collagen sponge containing 5 million human-derived bone marrow cells (HBMCs) infected with the BMP-2-containing adenovirus. In Group II, 5 animals were implanted with a collagen sponge containing 5 million HBMCs, which had been infected with an adenovirus containing the cDNA for the lacZ gene. In Group III, 5 animals were implanted with a collagen sponge containing 5 million uninfected HBMCs. In Group IV, 5 animals were implanted with a collagen sponge alone. All animals were killed at 12 weeks. OBJECTIVES: The purpose of this study was to assess the ability of HBMCs infected with a BMP-2 adenovirus to induce a posterolateral spine in an athymic rat model. SUMMARY OF BACKGROUND DATA: High pseudarthrosis rates after attempted spinal arthrodesis as well as the morbidity associated with iliac crest bone graft harvest make alternative bone graft materials desirable. Alternatives include allograft bone, demineralized bone matrices, and more recently, recombinant bone morphogenetic proteins. However, high doses of the recombinant protein are required, and a single dose of recombinant protein may not induce a sufficient osteoinductive response in all patients. An alternative strategy is to genetically manipulate cells to overexpress a bone morphogenetic protein. METHODS: HBMCs grown in culture were infected with an adenovirus containing the cDNA for BMP-2 (AdBMP-2) or the gene for beta-galactosidase (AdlacZ). Cells were implanted on the decorticated transverse processes of L4-L5 as previously described. Rats were assessed by radiographs at 4-week intervals and were killed at 12 weeks. After death, spines were explanted and assessed by manual palpation and histologic analysis. RESULTS: Eight of eight rats implanted with AdBMP-2-infected HBMCs (Group I) were fused by radiographic evaluation and manual palpation at 12 weeks. Control groups consisted of: 5 rats implanted with the collagen sponge alone (Group II), 5 rats implanted with a collagen sponge and 5 million uninfected HBMCs (Group III), and 5 rats implanted with HBMCs infected with AdlacZ (Group IV). None of the rats in the control groups (0 of 15) developed a fusion at L4-L5. CONCLUSION: This study demonstrates that human-derived bone marrow cells can be infected with a BMP-2-containing adenovirus and produce sufficient bone in vivo to fuse the lumbar spine.

Adenoviridae↗
PubMed2005

Cemented femoral revision: lest we forget.

Cemented femoral revisions can provide durable fixation when used for specific indications. These indications include elderly patients with minimal bone loss or large femoral canals and the cement-within-cement technique where a new femoral component is cemented into an intact cement mantle.

Arthroplasty, Replacement, Hip↗
PubMed2005

Lentivirus-mediated gene transfer induces long-term transgene expression of BMP-2 in vitro and new bone formation in vivo.

We examined the potential of ex vivo gene therapy to enhance bone repair using lentiviral vectors encoding either enhanced green fluorescent protein (EGFP) as a reporter gene or bone morphogenetic protein-2 (BMP-2) downstream of either the cytomegalovirus immediate early (CMV) promoter or the murine leukemia virus long terminal repeat (RhMLV) promoter derived from a murine retrovirus adapted to replicate in a rhesus macaque. In vitro, rat bone marrow stromal cells (BMSCs) transduced with Lenti-CMV-EGFP or Lenti-RhMLV-EGFP demonstrated over 90% transduction efficiency at 1 week and continued to demonstrate stable expression for 8 weeks. ELISA results demonstrated that lentivirus-mediated gene transfer into BMSCs induced stable BMP-2 production in vitro for 8 weeks. Increased EGFP and BMP-2 production was noted with the RhMLV promoter. In addition, we implanted BMSCs transduced with Lenti-RhMLV-BMP-2 into a muscle pouch in the hind limbs of severe combined immune deficient mice. Robust bone formation was noted in animals that received Lenti-RhMLV-BMP-2 cells at 3 weeks. These results demonstrate that lentiviral vectors expressing BMP-2 can induce long-term gene expression in vitro and new bone formation in vivo under the control of the RhMLV promoter. Prolonged gene expression may be advantageous when developing tissue engineering strategies to repair large bone defects.

Animals↗
PubMed2005

The efficacy of different commercially available demineralized bone matrix substances in an athymic rat model.

OBJECTIVE: Bone graft substitutes have been developed because there is a limited supply of autogenous graft and the harvesting of iliac crest bone graft is associated with significant morbidity. Currently, there are a number of different commercially available demineralized bone matrix (DBM) products available that have been prepared by different methods and have different carriers. The objective of this study was to compare eight different commercially available DBM products. METHODS: Eight different DBMs were used to attempt a spinal fusion between the L4-L5 transverse processes in athymic rats. There were 10 rats in each group, and 5 rats were killed at both 4 and 8 weeks. Radiographic and histologic analyses were performed. Manual palpation testing was also performed. RESULTS: At 4 weeks, Osteofil Paste had the highest radiographic scores, whereas Grafton Putty had the best radiographic scores at 8 weeks. Conversely, the spines implanted with Allomatrix had the lowest radiographic scores at both 4 and 8 weeks. In regard to forming a spinal fusion confirmed by manual palpation, Osteofil Paste was the most effective at 4 weeks, whereas Grafton Flex and Grafton Putty had the highest rate of fusion at 8 weeks. Conversely, the lowest rates of fusion were seen in the Allomatrix and Grafton Crunch groups. Statistical analysis showed that there were significant differences among the groups seen on radiographs and by manual palpation. Qualitative differences could be appreciated between the groups histologically. CONCLUSION: Significant differences exist among commercially available DBMs in forming a spinal fusion in an athymic rat.

Animals↗
PubMed2005

Tissue-engineered bone from BMP-2-transduced stem cells derived from human fat.

BACKGROUND: Progenitor cells capable of induction into multiple mesenchymal lineages have been isolated from human liposuction aspirates. These cells, named processed lipoaspirate cells, have previously shown in vitro osteogenic capacity. The purpose of this study was to examine the in vivo bone induction capacity of bone morphogenetic protein-2 (BMP-2)-transduced processed lipoaspirate cells using adipose tissue from multiple harvest sites. METHODS: Processed lipoaspirate cells extracted from human abdominal and buttock liposuction aspirates (n = 5) and from infrapatellar fat pads (n = 5) were placed in osteogenic media containing Dulbecco's Modified Eagle Medium with 10% fetal bovine serum supplemented with 50 muM ascorbic acid-2-phosphate and 10 mM beta-glycerol phosphate. Half of these cells were transfected with an adenovirus carrying the cDNA for bone morphogenetic protein-2 (adBMP-2). These transfected cells were then seeded onto collagen I matrices at a concentration of 2 x 10 cells/matrix and were placed into the hind limbs of severe combined immunodeficient mice (n = 10). Nontransfected processed lipoaspirate cells were placed in the contralateral limb as a control. After 6 weeks, specimens were analyzed by radiographs, densitometry, and hematoxylin and eosin and von Kossa staining. RESULTS: The average number of cells extracted from the abdominal/buttock lipoaspirates was 3.4 x 10 cells/100 ml fat aspirate and 5.5 x 10 cells per infrapatellar fat pad (average volume, 20.6 cc). All 10 BMP-2 transfected processed lipoaspirate constructs produced abundant radiographic and histologic bone. The bone was adequately mineralized and was beginning to establish a marrow cavity. There was no quantitative difference in bone production between harvest sites [mean, 2.0 +/- 0.1 aluminum units (knee) versus 2.1 +/- 0.1 aluminum units (abdomen/buttock); p = 0.14]. No bone was produced in the negative controls. CONCLUSIONS: Multipotential processed lipoaspirate cells can be extracted from adipose tissue harvested from liposuction aspirates or from the infrapatellar fat pad of the knee. Processed lipoaspirate cells can be transduced with the BMP-2 gene to produce abundant in vivo bone. These cells appear to be clinically useful for bone tissue engineering applications either as osteoprogenitor cells or as delivery vehicles for BMP-2.

Adenoviridae↗
PubMed2005

Oral direct thrombin inhibitor ximelagatran compared with warfarin for the prevention of venous thromboembolism after total knee arthroplasty.

BACKGROUND: Warfarin, which requires coagulation monitoring, is associated with relatively high rates of thromboembolism despite providing adequate prophylaxis. This study compared an oral direct thrombin inhibitor, ximelagatran, with warfarin in order to evaluate the safety and efficacy of the medication for the prevention of venous thromboembolism in patients undergoing total knee arthroplasty. METHODS: Following surgery, patients were randomly assigned to fixed-dose oral ximelagatran (36 mg twice daily) or warfarin (target international normalized ratio, 2.5), both administered for seven to twelve days in a double-blind, double-dummy design. Warfarin was initiated on the evening of the day of surgery, and ximelagatran, on the morning after surgery. The primary efficacy end point was the incidence of asymptomatic deep-vein thrombosis determined by bilateral venography, objectively confirmed symptomatic deep-vein thrombosis or pulmonary embolism, and death from all causes during treatment. RESULTS: Adequate venograms or confirmed symptomatic events (efficacy population) were obtained for 1949 patients. Venous thromboembolism and death from all causes occurred in 22.5% (221) of 982 ximelagatran-treated patients and in 31.9% (308) of 967 warfarin-treated patients (p < 0.001). Proximal deep-vein thrombosis and pulmonary embolism were observed in 3.1% (thirty) and 0.2%, respectively, of the patients in the ximelagatran group and in 3.4% (thirty-three) and 0.4%, respectively, of the patients in the warfarin group. The six deaths from all causes included 0.3% (four) of the ximelagatran-treated patients and 0.2% (two) of the warfarin-treated patients. Major bleeding was noted in 1% (twelve) of the ximelagatran-treated patients and in 0.4% (five) of the warfarin-treated patients (p = 0.09). CONCLUSIONS: Oral ximelagatran (36 mg twice daily), administered without coagulation monitoring or dose adjustment and started the day after total knee arthroplasty, demonstrates superior efficacy compared with warfarin prophylaxis, with no wound complications and no significant difference with respect to bleeding events, although the rate of major bleeding events was greater with ximelagatran than with warfarin. LEVEL OF EVIDENCE: Therapeutic Level I.

Aged↗
PubMed2005

Prevention of venous thromboembolic disease after total hip and knee arthroplasty.

Patients undergoing total hip and knee arthroplasty are at increased risk for the development of venous thromboembolic disease, and there is general agreement that these patients require prophylaxis. The selection of a prophylactic agent involves a balance between efficacy and safety and often needs to be individualized for specific patients and institutions. Despite extensive research, the ideal agent for prophylaxis against deep venous thrombosis has not been identified. The results of randomized trials indicate that low-molecular-weight heparin, warfarin, and fondaparinux are the most effective prophylactic agents after total hip arthroplasty and that low-molecular-weight heparin, warfarin, fondaparinux, and pneumatic compression boots are the most effective agents after total knee arthroplasty. The duration of prophylaxis against deep venous thrombosis after total hip and knee arthroplasty remains controversial. Prophylaxis should be continued beyond hospital discharge. In the future, the determination of the duration of prophylaxis will be based on the risk stratification of individual patients. The practice of discharging patients from the hospital without prophylaxis, even when the decision is based on negative results of procedures that screen for the presence of deep venous thrombosis, is not cost-effective.

Anticoagulants↗
PubMed2004

Combined bone morphogenetic protein-2 and -7 gene transfer enhances osteoblastic differentiation and spine fusion in a rodent model.

UNLABELLED: To enhance the osteogenic activity of BMP, combination BMP2 and BMP7 gene transfer was performed. This approach led to a significant increase in osteoblastic differentiation of mesenchymal precursors compared with single BMP gene transfer in vitro. When tested in 78 rats, combination gene transfer enhanced mechanically stable spine fusion and bone formation rate versus single BMP gene transfer. INTRODUCTION: Although clinical bone morphogenetic protein (BMP) therapy is effective, required doses are very high. Previous studies have suggested that the co-expression of two different BMP genes can result in the production of heterodimeric BMPs that may be more potent than homodimers. In this study, combined BMP2 and BMP7 gene transfer was performed to test whether this approach improves osteoblastic differentiation and bone formation compared with single BMP gene transfer. MATERIALS AND METHODS: A producer cell (A549) was co-transfected with adenovirus vectors encoding BMP2 (AdBMP2) and BMP7 (AdBMP7) or, as controls, each vector alone, AdNull (with no transgene) or no virus. Supernatants were compared for their ability to stimulate osteoblastic differentiation of C2C12 myoblasts and MC3T3-E1 pre-osteoblasts. In a rat posterolateral spine fusion model, co-administration of AdBMP2 and AdBMP7 was compared with treatment with each vector alone, AdNull or no virus in 78 rats. The spines were assessed 8 weeks after surgery for radiographic and mechanical fusion, bone formation, and mineralization. RESULTS: BMP2 and BMP7 were co-precipitated from supernatants of cells co-transfected with AdBMP2 and AdBMP7, indicating the presence of BMP2/7 heterodimer. Supernatants of co-transfected cells containing relatively low doses (7-140 ng/ml) of BMPs induced osteocalcin expression and alkaline phosphatase activity in both C2C12 and MC3T3-E1 cells, that were up to 6- and 40-fold higher, respectively, than levels induced by maximal doses (200-1000 ng/ml) of either BMP2 or BMP7 alone. In the spine fusion model, co-administration of AdBMP2 and AdBMP7 resulted in a significantly greater number of mechanically stable fusions and also 2-fold higher mineralization rate and bone volume in the fusion mass versus single BMP gene transfer (p < 0.02, all comparisons). CONCLUSION: Combined BMP2 and BMP7 gene transfer is significantly more effective in inducing osteoblastic differentiation and spine fusion than individual BMP gene transfer.

3T3 Cells↗
PubMed2004

Genetic modification of stem cells to enhance bone repair.

Orthopaedic surgeons are often faced with difficult bone loss problems. Conventional bone grafting is usually accomplished with autogenous iliac crest bone graft that provides osteogenic cells, osteoinductive growth factors, and an osteoconductive matrix. Cadaveric bone allograft and bone graft substitutes are inferior to autogenous bone graft because they fail to supply osteogenic cells or a significant amount of osteoinductive growth factors. Recombinant growth factors such as bone morphogenetic protein-2 and osteogenic protein-1 are currently in clinical use but these proteins require supraphysiologic dosing and considerable expense while failing to provide a sustained osteoinductive signal at the implantation site. Mesenchymal stem cells capable of differentiating into mesodermal tissues have been isolated and expanded in culture from several different sources including bone marrow, adipose tissue, and muscle. In the presence of appropriate growth factors these cells can differentiate into osteoblast lineage cells that will form bone in vitro and in vivo. Recent attention has focused on genetic modification of mesenchymal stem cells to both produce and respond to osteogenic growth factors with the goal of developing a tissue engineering strategy for bone repair. This review examines the current potential and limitations of these cellular systems for bone repair.

Animals↗
PubMed2004

Core decompression for osteonecrosis of the hip.

The ultimate goal of treatment of patients with osteonecrosis of the hip is preservation of the femoral head. However, the development of a successful strategy to treat this disease has been difficult because neither the etiology nor the natural history of osteonecrosis of the hip has been defined clearly. Core decompression of the hip is one of the most commonly done surgical procedures to treat the early stages of osteonecrosis of the femoral head. However, there is no general consensus among investigators regarding either the specific indications for this procedure, or the specific technique of core decompression that would optimize results. The data available suggest that core decompression is more effective than nonoperative treatment particularly for patients with limited involvement of the femoral head and with an area of sclerosis surrounding the necrotic bone. The combination of core decompression with the use of osteoinductive or angiogenic agents to enhance bone formation and repair may enhance the results of this surgical procedure in the future.

Decompression, Surgical↗
PubMed2004

New technology and the orthopaedic surgeon: are you protecting your patients?

The treatment of patients with musculoskeletal disease will be revolutionized during the next two decades by advances in technology. Orthopaedic surgeons are eager to incorporate new technology into their practices to improve patient outcomes and practice efficiency. However, as the orthopaedic community embraces new technology and innovative surgical procedures, there is an increased need to consider issues of patient safety and to determine the best way to incorporate technology into our practices.

Conflict of Interest↗
PubMed2004

Treatment of osteonecrosis of the femoral head with core decompression and human bone morphogenetic protein.

A retrospective evaluation was done of 15 patients (17 hips) with symptomatic osteonecrosis of the hip treated with core decompression combined with an allogeneic, antigen-extracted, autolyzed fibula allograft and 50 mg of partially purified human bone morphogenetic protein and noncollagenous proteins. The average duration of clinical followup of the patients was 53 months (range, 26-94 months). The osteonecrotic involvement of the hip was classified by plain radiographs using a modification of the Ficat staging system and MRI evaluations. Fifteen hips were classified as Ficat Stage IIA, one hip (one patient) was classified as Ficat Stage IIB, and one hip (one patient) was classified as Ficat Stage III. Fourteen hips had involvement of 50% or less of the femoral head and 2/3 or less involvement of the weight-bearing surface of the femoral head, based on a magnetic resonance imaging evaluation. The procedures were a clinical success in 14 of 15 hips (93%; 13 patients) with Stage IIA disease. Three of 17 hips (three patients) had radiographic progression (Ficat Stages IIA, IIB, and III) of the femoral head and were converted to total hip replacements. Only one of seven hips (six patients) with 50% or less involvement of the femoral head and between 1/3 and 2/3 of the weightbearing surface of the femoral head developed radiographic progression of the femoral head. There was no radiographic progression in the 3 hips with less than 1/3 involvement of the weightbearing surface of the femoral head. Further evaluation of the potential efficacy of bone morphogenetic protein is required in randomized trials.

Adult↗
PubMed2004

Osteoinductivity of commercially available demineralized bone matrix. Preparations in a spine fusion model.

BACKGROUND: Although autogenous bone is the most widely used graft material for spinal fusion, demineralized bone matrix preparations are available as alternatives or supplements to autograft. They are prepared by acid extraction of most of the mineralized component, with retention of the collagen and noncollagenous proteins, including growth factors. Differences in allograft processing methods among suppliers might yield products with different osteoinductive activities. The purpose of this study was to compare the efficacy of three different commercially available demineralized bone matrix products for inducing spinal fusion in an athymic rat model. METHODS: Sixty male athymic rats underwent spinal fusion and were divided into three groups of eighteen animals each. Group I received Grafton Putty; Group II, DBX Putty; and Group III, AlloMatrix Injectable Putty. A control group of six animals (Group IV) underwent decortication alone. Six animals from each of the three experimental groups were killed at each of three intervals (two, four, and eight weeks), and the six animals from the control group were killed at eight weeks. At each of the time-points, radiographic and histologic analysis and manual testing of the explanted spines were performed. RESULTS: The spines in Group I demonstrated higher rates of radiographically evident fusion at eight weeks than did the spines in Group III or Group IV (p < 0.05). Manual testing of the spines at four weeks revealed variable fusion rates (five of six in Group I, two of six in Group II, and none of six in Group III). At eight weeks, all six spines in Group I, three of the six in Group II, and no spine in Group III or IV had fused. Histologic analysis of the spines in Groups I, II, and III demonstrated varying amounts of residual demineralized bone matrix and new bone formation. Group-I spines demonstrated the most new bone formation. CONCLUSIONS: This study demonstrated differences in the osteoinductive potentials of commercially available demineralized bone matrices in this animal model.

Animals↗
PubMed2004

Hyaluronan therapy: looking toward the future.

Hyaluronan therapy has numerous medical applications, including the treatment of joint arthropathies, wound healing, prevention of postsurgical adhesions, treatment of urinary incontinence, ophthalmic surgery, and tissue augmentation and engineering. Studies have been conducted and are ongoing to evaluate the efficacy of intra-articular hyaluronans in disease modification in osteoarthritis of the knee; efficacy in disease states other than osteoarthritis; as adjunct therapy after joint surgery; and in joints other than the knee--namely the shoulder, hand, hip, temporomandibular joint, spine, foot, and ankle. Preliminary results have been promising and parallel what has been found in treatment of osteoarthritis of the knee. Research also continues into the development of chemically modified derivatized hyaluronan to optimize responses and enhance duration of action, as well as to expand the uses of this therapeutic modality.

Animals↗
PubMed2004

Restoring articular cartilage in the knee.

Following damage or injury, as well as normal wear and tear, articular cartilage in adults has limited healing potential. Repair of cartilage is dependent on the extent and depth of the injury, its location, and the surviving chondrocytes and extracellular matrix. The ultimate goal of cartilage repair is to restore the normal composition and matrix of the cartilage, but for most patients this is not feasible. In these cases, filling the defect using interventions that provide adequate, albeit not optimal, functionality and pain relief is desirable. Therefore, a more realistic goal in these patients may be restoration of their respective activity levels and the delay or avoidance of prosthetic replacement. Depending on the age, activity level, and degree of cartilage damage, several methods to decrease pain and attempt cartilage repair are available; these include lavage and debridement, abrasion arthroplasty, and tissue and cell transplantation. Future strategies for cartilage repair may involve tissue engineering techniques, possibly coupled with specific growth factors. Randomized clinical trials must be established.

Cartilage, Articular↗