transforming-growth-factor-beta and Osteonecrosis

Recombinant human bone morphogenetic protein-2 is an osteoinductive protein that plays a pivotal role in bone growth and regeneration. Several hundred studies were conducted in the past 7 years in numerous animal models to establish unequivocally the efficacy, safety, mechanism of action, pharmacokinetics, and surgical handling properties of recombinant human bone morphogenetic protein-2, building a solid foundation for clinical development programs. Pilot clinical trials have shown the feasibility and safety of recombinant human bone morphogenetic protein-2 treatment, and defined the effective dose for its use in open long bone fractures and for augmentation or preservation of the alveolar bone in the dental ridge. Prospective observational clinical studies helped define clinical efficacy end points, identify significant variables, and estimate appropriate population sample size for pivotal clinical trials. Pivotal clinical trials of recombinant human bone morphogenetic protein-2 are underway in patients with open tibial shaft fractures and in patients with a deficiency of the alveolar ridge.

Topics: Animals; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Clinical Trials as Topic; Disease Progression; Dose-Response Relationship, Drug; Fracture Healing; Fractures, Open; Humans; Osteogenesis, Distraction; Osteonecrosis; Recombinant Proteins; Tibial Fractures; Transforming Growth Factor beta; Treatment Outcome

Long non‑coding RNAs (lncRNAs) are crucial for the occurrence and development of numerous diseases. Although lncRNAs are involved in the biological activities of stem cells and play crucial roles in stem cell differentiation, the expression of specific lncRNAs during human bone marrow‑derived mesenchymal stem cell (hBMSC) osteogenic differentiation in osteonecrosis of the femoral head (ONFH) and their regulatory roles have not yet been fully elucidated. To the best of our knowledge, the present study is the first to characterize lncRNA expression profiles during hBMSC osteogenic differentiation in ONFH using microarray analysis and RT‑qPCR to confirm the microarray data. A total of 24 downregulated and 24 upregulated lncRNAs were identified and the results of RT‑qPCR were found to be consistent with those of microarray analysis. Bioinformatics analyses, using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases, were conducted to explore the possible mechanisms and identify the signaling pathways that the lncRNAs are involved in. GO analysis revealed significant changes in the intracellular organelle, Ras protein signal transduction and transferase activity. KEGG pathway analysis revealed that the lncRNAs were closely associated with fatty acid metabolism, apoptosis and the TGF‑β signaling pathway. The overexpression of MAPT antisense RNA 1 (MAPT‑AS1) was found to promote osteogenesis and inhibit the adipogenesis of hBMSCs at the cellular and mRNA levels. On the whole, the findings of the present study identified the lncRNAs and their roles in hBMSCs undergoing osteogenic differentiation in ONFH and provide a new perspective for the pathogenesis of ONFH.

Topics: Adipogenesis; Bone Marrow; Bone Marrow Cells; Cell Differentiation; Computational Biology; Fatty Acids; Femur Head; Gene Expression Profiling; Humans; Mesenchymal Stem Cells; Osteogenesis; Osteonecrosis; RNA, Long Noncoding; RNA, Messenger; Signal Transduction; Stem Cells; tau Proteins; Transforming Growth Factor beta; Up-Regulation

The purpose of this study was to compare the clinical outcomes of impacted bone graft with or without recombinant human bone morphogenetic protein-2 (rhBMP-2) for osteonecrosis of the femoral head (ONFH). We examined the effect of bone-grafting through a window at the femoral head-neck junction, known as the "light bulb" approach, for the treatment of ONFH with a combination of artificial bone (Novobone) mixed with or without rhBMP-2. A total of 42 patients (72 hips) were followed-up from 5 to 7.67 years (average of 6.1 years). The patients with and without BMP were the first group (IBG+rhBMP-2) and the second group (IBG), respectively. The clinical effectiveness was evaluated by Harris hip score (HHS). The radiographic follow-up was evaluated by pre-and postoperative X-ray and CT scan. Excellent, good, and fair functions were obtained in 36, 12, and 7 hips, respectively. The survival rate was 81.8% and 71.8% in the first and second group, respectively. However, the survival rate was 90.3% in ARCO stage IIb, c, and only 34.6% in ARCO stage IIIa (P<0.05). It was concluded that good and excellent mid-term follow-up could be achieved in selected patients with ONFH treated with impacted bone graft operation. The rhBMP-2 might improve the clinical efficacy and quality of bone repair.

Topics: Adult; Bone Morphogenetic Protein 2; Bone Transplantation; Debridement; Female; Femur Head Necrosis; Follow-Up Studies; Humans; Male; Middle Aged; Osteonecrosis; Prognosis; Recombinant Proteins; Retrospective Studies; Survival Rate; Tomography, X-Ray Computed; Transforming Growth Factor beta; Young Adult

The study included 15 patients with purulent inflammatory diseases of maxillofacial area and 25 patients with facial bone necrosis induced by synthetic drugs. Pro- and anti-inflammatory cytokines levels in saliva and wound fluid were analyzed in two groups. The results proved cytokines to play important role in jaw necrosis induced by drugs containing red phosphorus.

Topics: Adult; Cytokines; Female; Humans; Illicit Drugs; Interleukin-10; Jaw Diseases; Male; Middle Aged; Morphine Derivatives; Osteonecrosis; Saliva; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Young Adult

Bisphosphonates are a class of agents used for treating osteoporosis and malignant bone metastases treatment. Osteonecrosis of the jaws is the main complication in a subset of patients receiving these drugs. Based on a growing number of case reports and institutional reviews, bisphosphonate therapy can cause exposed and necrotic bone that is isolated to the jaw. This clinical investigation is aimed at analyzing the clinical effect of recombinant human bone morphogenetic protein type 2 (rhBMP-2) application in patients affected by bisphosphonates-related osteonecrosis of the jaws undergoing surgery for necrotic bone removal.A case review was made of 20 patients. The rhBMP-2 in all the cases reported here was used alone with the collagen carrier without concomitant bone materials. The cases involved osteonecrotic lesions of the upper and lower jaws. A total dose of 4 to 8 mg of rhBMP-2 was delivered to the surgical site in concentrations of 1.5 mg/mL (depending on the size of lesion). Patients were followed up over a period ranging 6 to 12 months.Patients had successful healing of the necrotic area. New bone formation in the surgical area could be clinically evaluated by palpation at the end of 3 to 4 months and confirmed by radiographic examination at the end of 12 months.This study indicated that the use of rhBMP-2 without concomitant bone grafting materials was useful in promoting healing of bisphosphonates-related osteonecrosis of the jaws. The use of growth factors, particularly rhBMP-2, should be considered a therapeutic choice in patients affected by osteonecrosis of the jaws related to bisphosphonate therapy.

Topics: Bone Morphogenetic Protein 2; Combined Modality Therapy; Diphosphonates; Humans; Jaw Diseases; Osteonecrosis; Osteoporosis; Pain Management; Postoperative Complications; Recombinant Proteins; Transforming Growth Factor beta; Treatment Outcome; Wound Healing

Untreated osteonecrosis of the hip causes collapse of the femoral head and eventually leads to the development of premature degenerative arthritis. In order to reverse this late complication after the core decompression procedure, we studied three different types of carriers used to entrap recombinant human bone morphogenetic protein-2 (rhBMP-2) in terms of their performance in osteonecrosis regeneration and creeping substitution in Balb/C mice. The rhBMP-2 was loaded into PLGA-HAp microsphere in three different ways. We first verified the therapeutic dose in vitro using D1 and C2C12 cells. Then the individual performance of the three carrier preparations in vivo was examined by soft X-ray observation, histological analysis and immunostaining of bone tissue. In addition, the BMP-2 protein concentration activity in the serum was monitored. The results revealed that the bioactivity of rhBMP-2 released from a carrier with an ideal therapeutic dose was well maintained; this eventually helped to improve the healing and substitution of necrotic bone in vivo. These observations demonstrate that the in vivo performance of these newly developed rhBMP-2 delivery carriers correlates well with their in vitro release profiles. We concluded that sustained controlled-release of rhBMP-2 above a therapeutic dose could not only induce early callus wrapping of the necrotic bone but also produce neovascularization and substitution inside of the dead bone.

Topics: Adult; Animals; Biocompatible Materials; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Bone Regeneration; Cell Line; Drug Carriers; Humans; Implants, Experimental; Lactic Acid; Materials Testing; Mice; Mice, Inbred BALB C; Microspheres; Osteogenesis; Osteonecrosis; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Radiography; Recombinant Proteins; Tibia; Transforming Growth Factor beta; Young Adult

The purpose of this study was to evaluate the effect of rhBMP-2 on bone healing in patients who undergo high-risk ankle & hindfoot fusions.. Patients who underwent high-risk, elective ankle and hindfoot fusions treated with rhBMP-2 augmentation were reviewed for clinical outcomes and complications. A total of 112 fusion sites (69 patients) were reviewed for analysis. The mean age of the patients was 52 years (range, 21 to 84 years). There were 37 males (53%) and 32 females (47%). Forty-four patients (64%) were smokers and 13 patients (19%) were diabetic. A history of high-energy trauma was present in 47 (68%) patients and avascular necrosis of the talus was present in 22 patients (32%). Forty-five patients (65%) had multiple risk-factors. The exclusion criteria were peripheral vascular disease, infection, and patients who were not available for the usual follow-up protocol. Internal and/or external fixation was utilized for ankle and hindfoot fusions. Bone graft was used only for patients who had defects or malalignment. Postoperatively, nonweightbearing radiographs were taken every 2 to 4 weeks (3 views per site). When plain radiographic union was evident, a confirmatory CT scan was obtained.. Overall, 108 fusion sites went on to union (96% union rate) at a mean time of 11 weeks (as assessed by a CT scan) [ankle joint at 10 weeks; subtalar joint at 12.3 weeks; talonavicular joint at 12.7 weeks and calcaneocuboid joint at 10.9 weeks]. Different union times between ankle, subtalar, talonavicular, and calcaneocuboid joint were not significant (p = 0.2571, Kruskal-Wallis Test Nonparametric ANOVA). All sites: [No graft] vs. [Autograft] vs. [Allograft]: p = 0.2421 (Kruskal-Wallis Test Nonparametric ANOVA), were not statistically significant. Complications included nonunion in 5 of 112 joints in 3 patients (4% joint nonunion rate; 4% patient nonunion rate) [subtalar joint, n = 2; talonavicular joint, n = 1; and calcaneocuboid joint, n = 1]. Two patients had wound complications and one other patient had a deep infection; all were successfully treated with local wound care, negative-pressure dressings and antibiotics.. We believe rhBMP-2 is an effective adjunct for bone healing in patients who undergo high-risk ankle and hindfoot fusions. Low complication rates were observed in this study.

Topics: Adult; Aged; Aged, 80 and over; Ankle Injuries; Ankle Joint; Arthrodesis; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Cohort Studies; Female; Fracture Healing; Humans; Male; Middle Aged; Osteonecrosis; Recombinant Proteins; Retrospective Studies; Tarsal Joints; Transforming Growth Factor beta; Treatment Outcome; Young Adult

Most researchers believe that the peroxisome proliferative activated receptor gamma (PPARgamma-2) and bone morphogenetic protein receptor type II (BMPR2) play important roles in steroid-induced osteonecrosis (ON). However, the molecular mechanism of this process is still unclear. Recent studies indicate that steroid treatments cause adipocyte formation due to differentiation of mesenchymal stem cells, which then prevents osteoblast formation. This study examined PPARgamma-2, bone morphogenetic protein 2 (BMP2), and BMPR2 in patients with systemic lupus erythromatosus (SLE) who eventually developed ON after prolonged steroid treatment. The subjects of this experiment included 220 SLE patients who had undergone steroid treatment for at least 2 years. Fifty-five of the 220 patients were ON patients, and 165 were non-ON patients. Real-time PCR was performed to analyze the expression of the PPARgamma-2, BMP2, and BMPR2 mRNA in the peripheral blood of these patients. The results indicated that the expression of PPARgamma-2 mRNA increased 37% in the ON patients' peripheral blood, but the expression of BMPR2 mRNA decreased 57%. The average expression of the PPARgamma-2 mRNA in the ON patients was significantly higher than that in the non-ON patients (p = 0.044). Conversely, the expression of BMPR2 mRNA was significantly lower than that in non-ON patients (p = 0.036), but the expression of BMP2 mRNA did not significantly differ. This study demonstrated that the PPARgamma-2 and BMPR2 have important roles in the ON process after prolonged steroid administration in SLE patients; however, the detailed molecular mechanisms of this process require further study.

Topics: Adrenal Cortex Hormones; Adult; Bone Morphogenetic Protein 2; Bone Morphogenetic Protein Receptors, Type II; Bone Morphogenetic Proteins; Female; Gene Expression; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Male; Middle Aged; Osteonecrosis; PPAR gamma; Transforming Growth Factor beta