Retracted: Osteoprotegerin (OPG) Promotes Recruitment of Endothelial Progenitor Cells (EPCs) via CXCR4 Signaling Pathway to Improve Bone Defect Repair.

The Editors of Medical Science Monitor wish to inform you that the above manuscript has been retracted from publication due to concerns with the credibility and originality of the study, the manuscript content, and the Figure images. Reference: Rongfeng Zhang, Jianwei Liu, Shengpeng Yu, Dong Sun, Xiaohua Wang, Jingshu Fu, Jie Shen, Zhao Xie. Osteoprotegerin (OPG) Promotes Recruitment of Endothelial Progenitor Cells (EPCs) via CXCR4 Signaling Pathway to Improve Bone Defect Repair. Med Sci Monit, 2019; 25: 5572-5579. DOI: 10.12659/MSM.916838.

Osteoprotegerin (OPG) Promotes Recruitment of Endothelial Progenitor Cells (EPCs) via CXCR4 Signaling Pathway to Improve Bone Defect Repair.

BACKGROUND The aim of this study was to investigate the effect of using osteoprotegerin (OPG) to treat bone defects mediated by endothelial progenitor cell (EPC) recruitment and migration through the CXCR4 signaling pathway. MATERIAL AND METHODS The EPCs extracted from human peripheral blood were cultured in vitro and the expression of CXCR4 and its downstream p-AKT was monitored by the Western blot analysis after OPG treatment. Using the scratch wound healing test and Transwell assay, we assessed the variables influencing the effect of OPG on EPCs after pre-treatment with CXCR4 blocker (AMD3100) and PI3K blocker (Ly294002). After 4 weeks, the bone defect repair condition was estimated via micro-CT and staining with HE and Masson trichrome. Then, immunofluorescence staining was performed to assess angiogenesis in bone defects, while the expression of EPC marker and vascular endothelial growth factor receptor 2 (VEGFR2) was detected by immunohistochemical staining. RESULTS The EPCs treated with OPG had increased levels of CXCR4 and p-AKT. Moreover, the difference in EPC levels among groups in the scratch wound healing experiment and migration experiment indicated that the OPG treatment promoted cell migration and AMD3100 and LY294002 inhibited the function of OPG. In addition, OPG promoted angiogenesis and repair of bone defect in rats, and these effects were abolished by AMD3100 and LY294002 administration. CONCLUSIONS OPG enhanced the proliferation and migration of EPCs through the CXCR4 pathway and promoted angiogenesis and bone formation at bone defect sites.

Induced membrane technique for the treatment of chronic hematogenous tibia osteomyelitis.

BACKGROUND: Chronic hematogenous osteomyelitis often results from the improper treatment of acute hematogenous osteomyelitis. At present, there is lack of uniform standards for the treatment, and the clinical features of the disease are unclear. The purpose of this study was to explore the clinical efficacy and complications of chronic hematogenous tibia osteomyelitis treated with the induced membrane technique. METHODS: A retrospective analysis of the chronic hematogenous tibia osteomyelitis patients in our department admitted from January 2013 to February 2014 and treated with the induced membrane two-stage surgical technique was performed. The defects were filled with antibiotic-loaded polymethyl methacrylate (PMMA) cement after radical debridement, and bone grafts were implanted to repair the defects after 6 to 8 weeks. RESULTS: A total of 15 cases were admitted in this study, including 13 men and 2 women with a mean age of 34 years (6 to 51). The mean duration of bone infection was 142 months (3 to 361). All patients were cured with an average follow-up of 25 months (24 to 28). Radiographic bone union occurred in 5.3 months (3 to 8), and full weight bearing occurred in 6.7 months (4 to 10). No recurrence of infection was noted at the last follow-up. Two cases required repeated debridement before grafting due to recurrent infection. One patient had a small bone diameter due to insufficient grafting, and one patient had limitation of knee activity. CONCLUSIONS: The induced membrane technique for the treatment of chronic hematogenous tibia osteomyelitis is an effective and reliable method. Thorough debridement and wound closure at the first stage is essential for infection control as well as sufficient grafting at the second stage to ensure bone union.

Induced membrane technique combined with a retrograde intramedullary nail for the treatment of infected bone defects of the ankle.

In this study, we treated infected ankle bone defects with the induced membrane two-stage technique. The ankle was fused with a retrograde intramedullary nail in the second stage, and the aim of this study was to observe the clinical effect. We retrospectively enrolled patients with infected bone defects of the ankle admitted to our hospital between July 2016 and July 2018. In the first stage, the ankle was temporarily stabilized with a locking plate, and antibiotic bone cement was used to fill the defects after debridement. In the second stage, the plate and cement were removed, the ankle was stabilized with a retrograde nail, and tibiotalar-calcaneal fusion was performed. Then, autologous bone was used to rebuild the defects. The infection control rate, fusion success rate and complications were observed. Fifteen patients were enrolled in the study with an average follow-up of 30 months. Among them, there were 11 males and 4 females. The average bone defect length after debridement was 5.3 cm (2.1-8.7 cm). Finally, 13 patients (86.6%) achieved bone union without recurrence of infection, and 2 patients experienced recurrence after bone grafting. The average ankle-hindfoot function score (AOFAS) increased from 29.75 ± 4.37 to 81.06 ± 4.72 at the last follow-up. The induced membrane technique combined with a retrograde intramedullary nail for the treatment of infected bone defects of the ankle after thorough debridement is an effective treatment method.

Induced membrane technique versus one-stage autografting in management of atrophic nonunion of long bone in the lower limb: clinical and health burden outcomes.

OBJECTIVE: In this study, we aimed to compare the outcomes of the two-stage induced membrane technique (IMT) and one-stage autografting in the treatment of aseptic atrophic nonunion in lower limb long bones. METHODS: From January 2014 to January 2022, we reviewed all surgically treated long bone nonunion patients, including patients aged 18 years or older with atrophic nonunion, who were either treated with the two-stage induced membrane technique (IMT) or one-stage autografting. Outcome parameters interns of clinical, quality of life and healthcare burden were recorded and retrospectively analysed between the two treatment populations. The follow-up time was at least 1 year. RESULTS: In total, 103 patients who met the criteria for aseptic atrophic nonunion were enrolled. Among them, 41 (39.8%) patients were treated with two-stage IMT, and 62 (60.2%) patients were treated with one-stage autologous bone grafting. The follow-up time was 12 to 68 months, with an average of 28.4 months. The bone healing rate was comparable in both groups (IMT: 92.7% vs. one-stage grafting: 91.9%, P = 0.089) at 12 months post-operation, and the bone healing Lane-Sandhu score was superior in the IMT group (mean: 8.68 vs. 7.81, P = 0.002). Meanwhile, the SF-12 scores of subjective physical component score (PCS) (mean: 21.36 vs. 49.64, P < 0.01) and mental health component score (MCS) (mean: 24.85 vs. 46.14, P < 0.01) significantly increased in the IMT group, as well as in the one-stage grafting group, and no statistically significant difference was found within groups. However, the total hospital stays (median: 8 days vs. 14 days, P < 0.01) and direct medical healthcare costs (median: ¥30,432 vs. ¥56,327, P < 0.05) were greater in the IMT group, while the complications (nonunion 8, infection 3, material failure 2, and donor site pain 6) were not significantly different between the two groups (17.1% vs. 19.4, P = 0.770). CONCLUSION: The data indicate that two-stage method of IMT serves as an alternative method in treating atrophic nonunion; however, it may not be a preferred option, in comprehensive considering patient clinical outcomes and healthcare burden. More evidence-based research is needed to further guide clinical decision-making.

Radiological and clinical outcomes using induced membrane technique combined with bone marrow concentrate in the treatment of chronic osteomyelitis of immature patients.

AIMS: Treatment of chronic osteomyelitis (COM) for young patients remains a challenge. Large bone deficiencies secondary to COM can be treated using induced membrane technique (IMT). However, it is unclear which type of bone graft is optimal. The goal of the study was to determine the clinical effectiveness of bone marrow concentrator modified allograft (BMCA) versus bone marrow aspirate mixed allograft (BMAA) for children with COM of long bones. METHODS: Between January 2013 and December 2017, 26 young patients with COM were enrolled. Different bone grafts were applied to repair bone defects secondary to IMT procedure for infection eradication. Group BMCA was administered BMCA while Group BMAA was given BMAA. The results of this case-control study were retrospectively analyzed. RESULTS: Patient infection in both groups was eradicated after IMT surgery. As for reconstruction surgery, no substantial changes in the operative period (p = 0.852), intraoperative blood loss (p = 0.573), or length of hospital stay (p = 0.362) were found between the two groups. All patients were monitored for 12 to 60 months. The median time to bone healing was 4.0 months (interquartile range (IQR) 3.0 to 5.0; range 3 to 7) and 5.0 months (IQR 4.0 to 7.0; range 3 to 10) in Groups BMCA and BMAA, respectively. The time to heal in Group BMCA versus Group BMAA was substantially lower (p = 0.024). CONCLUSION: IMT with BMCA or BMAA may attain healing in large bone defects secondary to COM in children. The bone healing time was significantly shorter for BMCA, indicating that this could be considered as a new strategy for bone defect after COM treatment. Cite this article: Bone Joint Res 2021;10(1):31-40.

Management of surgical site infection post-open reduction and internal fixation for tibial plateau fractures.

AIMS: In contrast to operations performed for other fractures, there is a high incidence rate of surgical site infection (SSI) post-open reduction and internal fixation (ORIF) done for tibial plateau fractures (TPFs). This study investigates the effect of induced membrane technique combined with internal fixation for managing SSI in TPF patients who underwent ORIF. METHODS: From April 2013 to May 2017, 46 consecutive patients with SSI post-ORIF for TPFs were managed in our centre with an induced membrane technique. Of these, 35 patients were included for this study, with data analyzed in a retrospective manner. RESULTS: All participants were monitored for a mean of 36 months (24 to 62). None were subjected to amputations. A total of 21 patients underwent two-stage surgeries (Group A), with 14 patients who did not receive second-stage surgery (Group B). Group A did not experience infection recurrence, and no implant or cement spacer loosening was noted in Group B for at least 24 months of follow-up. No significant difference was noted in the Lower Extremity Functional Scale (LEFS) and the Hospital for Special Surgery Knee Score (HSS) between the two groups. The clinical healing time was significantly shorter in Group B (p＜0.001). Those with longer duration of infection had poorer functional status (p＜0.001). CONCLUSION: Management of SSI post-ORIF for TPF with induced membrane technique combined with internal fixation represents a feasible mode of treatment with satisfactory outcomes in terms of infection control and functional recovery. Cite this article: Bone Joint Res 2021;10(7):380-387.

Risk factors associated with recurrence of extremity osteomyelitis treated with the induced membrane technique.

INTRODUCTION: Our aim was to observe the efficacy of the induced membrane technique in the treatment of extremity osteomyelitis and to analyse the causes of infection recurrence and its risk factors. METHODS: We retrospectively analysed 424 cases of extremity osteomyelitis treated with the induced membrane technique in our department between May 2013 and June 2017. Infection recurrence time, recurrence sites and other relevant information were collected, summarized, and analysed. RESULTS: A total of 424 patients were considered as "cured" of osteomyelitis after the first stage and the induced membrane technique was performed to rebuild the bone defects. After a mean follow-up of 31.6 (16-63) months, 52 patients had recurrence of infection, including 42 tibias and 10 femurs. The recurrence rate was 12.26%. Symptoms were relieved in 16 patients after intravenous antibiotic treatment. In the remaining 36 cases (8.49%), the infection was uncontrolled by intravenous antibiotics and surgical debridement was performed. The recurrence rate of infection of the tibia (16.22%) was higher than that of the femur (8.70%). The recurrence rate of post-traumatic osteomyelitis (14.66%) was significantly higher than that of hematogenous osteomyelitis (2.41%). Patients in whom Pseudomonas aeruginosa was isolated at the first stage had a recurrence rate of 28% (7/25), which was higher than that with the other isolated bacteria. Logistic regression analysis showed that repeated operations (≥3), post-traumatic osteomyelitis, and internal fixation at the first stage were risk factors for recurrence of infection, with odds ratios (ORs) of 2.30, 5.53 and 5.28 respectively. CONCLUSIONS: The induced membrane technique is an effective method in the treatment of extremity osteomyelitis, although infection recurs in some cases. Repeated operations, post-traumatic osteomyelitis, and internal fixation at the first stage were risk factors for recurrence of infection. P. aeruginosa isolated at the first stage, tibia osteomyelitis, the presence of sinus, or flaps may also be associated with recurrence of infection.

Investigating clinical characteristics and prognostic factors in patients with chronic osteomyelitis of humerus.

BACKGROUND: Chronic osteomyelitis in the humerus, which has complex neuroanatomy and a good soft tissue envelope, represents a unique clinical challenge. However, there are relatively few related studies in the literature. This article retrospectively reviewed a large case series with the aims of sharing our management experiences and further determining factors associated with the outcomes. METHODS: Twenty-eight consecutive adult patients with a mean age of 36 years were identified by reviewing the osteomyelitis database of our clinic centre. The database was used to prospectively identify all osteomyelitis cases between 2013 and 2017, and all data then was retrospectively analysed. RESULTS: The mean follow-up period was 35 months (range 24-60). The aetiology was trauma in 43% (12) of the patients and haematogenous in 57% (16) of the patients, and Staphylococcus aureus was a solitary agent in 50% (14) of the patients. Host-type (Cierny's classification) was IA in 8, IIIB in 11 and IVB in 9 patients. All patients required debridement followed by the placement of a temporary antibiotic-impregnated cement spacer (rod). Seventeen patients received a cement-coated plate for internal fixation after debridement, and 13 patients needed bone grafts when the spacer was staged removed. All patients attained an infection-free bone healing state at the final follow-up. The final average DASH (disabilities of the arm, shoulder and hand) score was 18.14 ± 5.39, while 6 patients (two developed traumatic olecranarthritis, four developed radial nerve injuries) showed the lowest levels of limb function (p = 0.000) and were unemployed. Three patients (type I; significant difference between type I versus type III and type IV patients, p < 0.05) experienced recurrence after debridement and underwent a second revision, which was not related to the bone graft (p = 0.226) or plate fixation (p = 0.050). CONCLUSIONS: Humeral chronic osteomyelitis can be treated with general surgery and anti-infective therapy; medullary (type I) infection presents a challenge, and the antibiotic-coated cement plate provides favourable fixation without increasing recurrence of infections. Clinicians should be aware of potential iatrogenic nerve injuries when treating these patients with complicated cases, and an experienced surgeon may improve the outcome.

Induced membrane technique: Advances in the management of bone defects.

Management of bone defects caused by trauma, osteomyelitis, and tumors is challenging, with many controversies over the optimal reconstruction method. Masquelet discovered induced membrane in management of large diaphyseal defects accidentally, and developed this technique with a concept of induced membrane. Induced membrane technique holds great potential for the reconstruction of bone defects, alternatively to manage this clinical challenge quiet easily. Induced membrane has unique structural characteristics and biological properties, which render this technique has an advantage of the time to bone healing is relatively independent of the length of bone defect. Herein, we reviewed the latest advances made in induced membrane technique and highlighted the concept of induced membrane in the management of bone defects.

Induced membrane technique combined with two-stage internal fixation for the treatment of tibial osteomyelitis defects.

INTRODUCTION: The purpose of this study was to observe the effects of induced membrane technique combined with two-stage internal fixation in the treatment of tibial osteomyelitis defects. METHODS: A retrospective analyses for 67 cases of tibialosteomyelitis defects were admitted to our department between September 2012 to February 2015, which were treated with induced membrane technique. At the first stage, implanted with a PMMA cement spacer in the defects after radical debridement and fixed with reconstructive locked plate. Bone grafting and exchanged the plate with intramedullary nail at the second stage. RESULTS: In current study, all patients were followed up for 18-35 months. Sixty-six patients achieved bone union with the average radiographic and clinical healing times of 5.55±2.19 and 7.45±1.69months, respectively. Seven patients required a second debridement before grafting, while four patients experienced a recurrence of infection or a relapse following second stage treatment. Twelve patients experienced either knee or ankle dysfunctions and 2 patients faced delayed wound healing. Donor site complications includes pain and infection were found in 7 and 3 patients, respectively with delayed stress fracture in 1 patient only. CONCLUSIONS: Induced membrane technique for the treatment of tibial osteomyelitis defects, seems a reliable method. The use of reconstructive locked plate as a temporary internal fixation at the first stage and exchanged with intramedullary nail at the second stage, potentially achieves good clinical efficacy. Care should be taken to restore the joint function especially in distal tibia.

Current data on extremities chronic osteomyelitis in southwest China: epidemiology, microbiology and therapeutic consequences.

The current study was designed to explore the epidemiology of extremities chronic osteomyelitis, its prognosis and the complications of the treatment methods being used in southwest China. The data from osteomyelitis patients treated at the Department of Orthopaedics, Southwest Hospital, China between May 2011 and September 2016 were collected and analysed. The study comprised 503 admitted patients, of which 416 males and 87 were females, with an average age of 40.15 ± 5.64 years. Approximately 356 cases were followed for more than 18 months; the average bone union time was 6.24 ± 0.76 months in 94.1% (335) patients, and infections were almost controlled in 93.8% patients. The rate of infection control with the induced membrane technique was higher than with the I-stage free bone graft. Iliac infection was the main complication of the induced membrane technique, and impaired joint activity was the main complication of I-stage free bone grafts. In southwest China, the incidence of haematogenous osteomyelitis, caused mainly by Staphylococcus aureus, remains very high. The speed of bone defect repair and the rate of infection control with the induced membrane technique were superior to those of I-stage free bone grafts. Internal fixation should be given priority because it offers reduced complications with no increase in the recurrence of infection.

Two stage management of Cierny-Mader type IV chronic osteomyelitis of the long bones.

INTRODUCTION: Cierny-Mader (C-M) type IV chronic osteomyelitis represents a complex clinical challenge with permeation of extensive bone and soft tissue involvement. Aggressive debridement through viable tissue margin includes en bloc resection improves the odds of eradication of infection, which creates large bone and soft tissue loss in treating this type of osteomyelitis. The potentially large defects increase reconstruction problems with traditional reconstruction technique. The newly staged induced membrane technique presents length-independent, potential as an alternative reconstruction method for segmental bone defects due to type IV chronic osteomyelitis. The purpose of this study was to assess the result and related factors of C-M type IV chronic osteomyelitis treated with staged methods of aggressive debridement and induced membrane technique. METHODS: From January 2012 to January 2014, 36 consecutive adult patients of C-M type IV chronic osteomyelitis were treated by this staged method in our clinical center with a minimum of 2-years follow-up. The clinical and imaging results were retrospectively analyzed. RESULTS: Five patients had a second debridement and eight needed a local flap transfer to cover the wound in the first stage. Patients formed a mean of 5.5cm (range: 2-10.9) segmental bone defect; Sixteen patients had autograft and twenty had autograft mixed allograft in the second stage. The mean follow-up time was 29.5 months (range: 24-45). No patients required amputation. Bone union was achieved in all patients. Clinical eradication of osteomyelitis was achieved in 35 (97%) patients, 35 (97%) patients were able to walk independently, and 31patients (86%) returned to work. Patients returned to a mean of 82% (46.3%-100%) lower extremity function. Bone union time was not dependent on the length of bone defect, but associated with the infection site (p=0.005) and age (p=0.005). CONCLUSIONS: Staged methods of aggressive debridement and induced membrane technique seems to be a simple, reliable and effective for the treatment of C-M type IV chronic osteomyelitis. Advanced age and poor soft tissue envelope may have adverse affects and are relative contraindications. The combined assessment and management of such patients with a plastic surgeon are advocated.

Immunohistochemical localization of steroid receptor coactivators in chondrosarcoma: an in vivo tissue microarray study.

Chondrosarcoma is the second most common type of primary bone malignancy following up osteosarcoma, characterized by resistance to conventional chemotherapeutic agents and radiation regimens. The p160 family members steroid receptor coactivator-1 and -3 (SRC-1 and SRC-3) have been implied in the regulation of cancer growth, migration, invasion, metastasis and chemotherapeutic resistance; but we still lack detailed information about the levels of SRCs in chondrosarcoma. In this study, expression of SRC-1 and SRC-3 in chondrosarcoma was examined by immunohistochemistry with tissue microarrays; the four score system (0, 1, 2 and 3) was used to evaluate the staining. The results showed that there were no gender-, site- or age-differences regarding the expression of SRC-1 or SRC-3 (p>0.05); organ (bone or cartilage) -differences were only detected for SRC-1 but not SRC-3 (p<0.05). Significant higher levels of SRC-1 and SRC-3 were detected in MDC and PDC when compared to WDC. Our study clearly demonstrated differentiation-dependant expression of SRC-1 and SRC-3 in chondrosarcoma, may be novel targets for the prognosis and/or treatment of chondrosarcoma, would have opened a new avenue and established foundation for studying chondrosarcoma.

MicroRNA-125b regulates osteogenic differentiation of mesenchymal stem cells by targeting Cbfß in vitro.

Differentiation of mesenchymal stem cells (MSCs) into a specific lineage is firmly and precisely regulated via crucial transcription factors and signaling cascades, but the accurate mechanisms still need to be revealed. MicroRNAs (miRNA) negativity regulates the target mRNA protein synthesis to regulate various kinds of biological processes. In the present study we investigate miRNAs mediated regulatory mechanisms of osteoblastic differentiation in C3H10T1/2 cells and we identified that the level of miR-125b expression was obviously decreased compared with undifferentiated ones during differentiation process. Subsequently, dual-luciferase reporter gene assay data demonstrated that miR-125b targets a putative binding site in the 3'-UTR of Cbfß gene, a key transcription factor for osteogenesis. We observed over and interferential expression of miR-125b down-regulate for Cbfß protein in C3H10T1/2 cells and the over-expression decrease the mRNA levels of three osteoblastic marker genes, alkaline phosphatase (ALP), osteocalcin (OCN), osteopontin (OPN) by BMP-2-induced, whereas, anti-miR-125b increased the expression of these marker genes and hence up-regulated mRNA levels of Cbfß. It is concluded from the result that miR-125b is a key regulatory factor of osteoblastic differentiation by directly targeting Cbfß and indirectly acting on Runx2 at an early stage osteoblastic differentiation.

Overexpression of steroid receptor coactivator-3 in bone cancers: an in vivo immunohistochemical study with tissue microarray.

Bone tissue is steroid-responsive and profoundly regulated by steroids and/or their receptors. Bone cancers (either primary or metastatic) belong to the most dangerous tumors. Previous studies have demonstrated overexpression of steroid receptor coactivator-3 (SRC-3) in many cancers, such as breast cancer, prostate cancer, thyroid cancer, functioning in the regulation of cancer cell proliferation, invasion, and metastasis. However, so far, the expression and function of SRC-3 in bone cancers have not yet been clarified. In this study, nickel-intensified immunohistochemistry was conducted using a commercial tissue microarray (with 94 cases of bone cancer tissue and 10 normal bone tissues), and the 4-scoring system was employed to evaluate the expression levels of SRC-3 immunoreactivity. The results showed that in normal bone tissue, levels of SRC-3 are almost negative (score=0), the total positivity (score=1-3) of SRC-3 immunoreactivities in bone cancers was 74.47%. There were no significant differences in gender, status (malignant or benign) or (mean) age (p>0.05). The percentage of positivity was 77.78% in osteogenic tumors, 58.82% in cartilage tumors, 70% in giant cell tumors, 100% in hematopoietic tumors, 77.78% in miscellaneous lesions, and 75% in miscellaneous tumors. Age related differences of SRC-3 immunoreactivities were detected in cartilage tumors and giant cell tumors (p<0.05). The above results clearly demonstrated a high frequency of overexpression of SRC-3 immunoreactivities in different bone cancers, indicating its potential roles in the prognosis and treatment of these cancers.