Interleukin-1 receptor antagonist enhances the therapeutic efficacy of a low dose of rhBMP-2 in a weight-bearing rat femoral defect model.

In the clinical treatment of fractures, rhBMP-2 administration is associated with a well-established profile of side-effects, including osteolysis and ectopic bone formation, which are driven by pro-inflammatory processes triggered by the use of high doses. Immunomodulatory strategies could minimize the incidence of side-effects by enabling the use of lower, and safer, rhBMP-2 doses. This study investigated whether interleukin-1 receptor antagonist (IL-1Ra) can enhance the therapeutic efficacy of a low dose of rhBMP-2 in a weight-bearing femoral fracture healing model. Exogenous IL-1Ra, in combination with rhBMP-2, was delivered using a collagen-hydroxyapatite scaffold (CHA) to attenuate IL-1ß produced in response to fracture. Femoral defects were treated with CHA scaffolds alone, or loaded with IL-1Ra (2.5 µg), rhBMP-2 (1 µg), IL-1Ra (2.5 µg) in combination with rhBMP-2 (1 µg). Bone healing was assessed over 14 weeks in comparison to control groups, empty defect, and a higher dose of rhBMP-2 (5 µg), which were recently demonstrated to lead to non-union, and successful bridging of the defect, respectively. The combination of IL-1Ra and rhBMP-2 led to significantly faster early bone formation, at both week 4 and 6, compared to a low dose of rhBMP-2 alone. By 14 weeks, the combination of IL-1Ra and a rhBMP-2 promoted full bridging of femurs, which were 3-fold more mechanically reliable compared to the femurs treated with a low dose of rhBMP-2 alone. Taken together, this study demonstrates that IL-1Ra can significantly enhance femoral bone healing when used in combination with a low dose of rhBMP-2. STATEMENT OF SIGNIFICANCE: Enabling the use of lower and safer doses of rhBMP-2, a potent inducer of bone formation, is of clinical relevance in orthopaedic medicine. In this study, the immunomodulatory interleukin-1 receptor antagonist (IL-1Ra) was investigated for its capacity to enhance the therapeutic efficacy of rhBMP-2 when used at lower doses in a weight-bearing femoral fracture healing model. The combination of IL-1Ra and rhBMP-2 led to significantly faster early bone formation, and resulted in more mechanically reliable healed femurs, compared to a low dose of rhBMP-2 alone. This demonstrates for the first time in a rat long bone healing model that IL-1Ra can significantly enhance bone healing when used in combination with a low dose of rhBMP-2.

MYBL2 disrupts the Hippo-YAP pathway and confers castration resistance and metastatic potential in prostate cancer.

Rationale: Resistance to androgen-deprivation therapy (ADT) associated with metastatic progression remains a challenging clinical task in prostate cancer (PCa) treatment. Current targeted therapies for castration-resistant prostate cancer (CRPC) are not durable. The exact molecular mechanisms mediating resistance to castration therapy that lead to CRPC progression remain obscure. Methods: The expression of MYB proto-oncogene like 2 (MYBL2) was evaluated in PCa samples. The effect of MYBL2 on the response to ADT was determined by in vitro and in vivo experiments. The survival of patients with PCa was analyzed using clinical specimens (n = 132) and data from The Cancer Genome Atlas (n = 450). The mechanistic model of MYBL2 in regulating gene expression was further detected by subcellular fractionation, western blotting, quantitative real-time PCR, chromatin immunoprecipitation, and luciferase reporter assays. Results: MYBL2 expression was significantly upregulated in CRPC tissues and cell lines. Overexpression of MYBL2 could facilitate castration-resistant growth and metastatic capacity in androgen-dependent PCa cells by promoting YAP1 transcriptional activity via modulating the activity of the Rho GTPases RhoA and LATS1 kinase. Importantly, targeting MYBL2, or treatment with either the YAP/TAZ inhibitor Verteporfin or the RhoA inhibitor Simvastatin, reversed the resistance to ADT and blocked bone metastasis in CRPC cells. Finally, high MYBL2 levels were positively associated with TNM stage, total PSA level, and Gleason score and predicted a higher risk of metastatic relapse and poor prognosis in patients with PCa. Conclusions: Our results reveal a novel molecular mechanism conferring resistance to ADT and provide a strong rationale for potential therapeutic strategies against CRPC.

Comparative Five-Year Surgical Outcomes of Open-Door versus French-Door Laminoplasty in Multilevel Cervical Spondylotic Myelopathy.

OBJECTIVE: To compare the five-year surgical outcomes between Open-Door laminoplasty (ODL) and French-Door laminoplasty (FDL) in the management of multilevel cervical spondylotic myelopathy (MCSM). METHODS: Sixty patients with MCSM, who were operated by ODL or FDL, were included in this study and followed up for at least 5 years. The average follow-up period was 69.2 ± 3.2 months. The modified Japanese Orthopaedic Association (mJOA) score and radiological assessments including the Cobb angle and cervical range of motion (ROM) were evaluated and compared before surgery and at the final follow-up. The incidence of postoperative complications and medical costs were also compared. RESULTS: Both ODL and FDL groups achieved significant improvements of the mJOA score in postoperative 5 years; the average recovery rate (RR) of the mJOA score in the ODL and FDL groups was 72.14 ± 6.97% and 69.53 ± 7.51%, respectively. No statistically significant differences regarding the pre- and postoperative mJOA score, the RR of the mJOA score, the loss and the loss rate of the Cobb angle, and the incidence of postoperative complications existed between ODL and FDL. The mean loss and the loss rate of cervical ROM in the FDL group (18.70 ± 8.91°, 41.08 ± 11.17%) were significantly higher than those of the ODL group (13.81 ± 8.62°, 31.47 ± 12.43%) (P < 0.05). FDL reduced medical costs more greatly than ODL (33014.37 ± 3424.12 China Yuan versus 82096.62 ± 7093.07 China Yuan, P < 0.001). CONCLUSIONS: Both ODL and FDL are effective for MCSM. The 5-year neurological results are similar between the two groups. ODL trends to be superior to FDL in postoperative preservation of cervical ROM while FDL reduced medical costs more greatly.