Objective: Insulin‐like growth factor binding protein 3 (IGFBP‐3) is known to interfere with the NF‐κB signaling pathway, and it effectively promotes apoptosis in tumor cells by a variety of mechanisms. NF‐κB activation and apoptosis resistance of fibroblast‐like synoviocytes (FLS) play pivotal roles in rheumatoid arthritis (RA). This study was undertaken to evaluate whether IGFBP‐3 has antiarthritic effects.Methods: To deliver IGFBP‐3, we used an adenovirus containing IGFBP‐3 complementary DNA (AdIGFBP‐3) or IGFBP‐3 mutant that is devoid of IGF binding affinity but retains IGFBP‐3 receptor binding ability (AdmtIGFBP‐3). The regulatory roles of IGFBP‐3 in inflammation and bone destruction were investigated in mice with collagen‐induced arthritis (CIA).Results: IGFBP‐3 levels were significantly higher in patients with RA than in those with osteoarthritis (OA) and were notably higher in patients with active RA. AdIGFBP‐3 suppressed NF‐κB activation, chemokine production, and matrix metalloproteinase secretion induced by tumor necrosis factor α (TNFα) in RA FLS. AdIGFBP‐3 sensitized RA FLS to TNFα‐induced apoptosis in vitro and also significantly increased apoptosis in an in vivo model of Matrigel implants engrafted into immunodeficient mice. AdIGFBP‐3–injected mice with CIA had attenuated arthritis severity and reduced radiologic and pathologic abnormalities. Moreover, AdIGFBP‐3 down‐regulated local and systemic levels of NF‐κB–targeted proinflammatory cytokines. Of note, RA FLS and mice with CIA treated with AdmtIGFBP‐3 exhibited similar effects as those treated with AdIGFBP‐3.Conclusion: Our results suggest that both the inflammatory response and bone destruction are reduced with blockage of NF‐κB activation and induction of apoptosis in RA FLS by IGFBP‐3. Therefore, IGFBP‐3 may have therapeutic potential in RA.

The pseudoreceptor BAMBI (bone morphogenetic protein and activin membrane-bound inhibitor), formerly known as NMA, is an inhibitor of the TGF-β signaling pathway. BAMBI exhibits structural homology to TGF-βRI but lacks an intracellular kinase domain. In most of the high-grade carcinomas, the degree of BAMBI expression is abnormally increased, which leads to the proliferation and metastasis of tumor cells. Recent studies have reported that BAMBI is involved in the Wnt-β-catenin pathway that regulates the proliferation and metastasis of tumor cells. However, little is known about the role of BAMBI and β-catenin in human osteosarcoma. Given the above background, we examined the role of BAMBI in the pathophysiology of osteosarcoma. Using immunohistochemical staining and western blot analysis, the degree of the expression of BAMBI and β-catenin was significantly higher in osteosarcoma specimens compared with normal tissues. With the overexpression of BAMBI, mediated by adenovirus, the degree of invasion and migration was significantly increased and the proliferation of U2-OS osteosarcoma cells was stimulated. Transwell analysis showed that BAMBI increased the invasion of osteosarcoma cells and upregulated the secretion of matrix metalloproteinases (MMPs), which was demonstrated by gelatin zymography. Fluorescence-activated cell sorting (FACS) analysis showed a significant arrest in cell cycle progression at G0/G1 in osteosarcoma cells transfected with siRNA targeting BAMBI. With the overexpression of BAMBI, mediated by the adenovirus, however, there was a decrease in the number of cells at G0/G1. Consistent with the findings that cell growth was increased, BAMBI promoted the transition from G0/G1 to G2/M in the osteosarcoma cells. Our results suggest that BAMBI plays a key role in the pathogenesis and progression of osteosarcoma by regulating the expression of β-catenin and other signaling molecules via the pathways involved in the regulation of the cell cycle. This relationship between BAMBI and its involvement in the regulation of the cell cycle would provide a possibility that the BAMBI may be a new target for gene therapy.

Lisha Yi, Haiqin Zhang, Huihui Sun, Lu Zhou, Ying Chen, Liqian Xuan, Yuanxi Jiang, and Shuchang Xu. J Neurogastroenterol Motil 1999;0:. https://doi.org/10.5056/jnm16089

Obesity is considered a clinical risk sign for Legg–Calvé–Perthes disease (LCPD). Leptin is primarily secreted by adipocytes, and it regulates adipose tissue mass and body weight. Furthermore, obesity is clearly associated with increased leptin levels. We investigated the roles of leptin and the soluble leptin receptor (sOB‐R) in LCPD. This matched case–control study included 38 male and 3 female patients with LCPD, and an equal number of age—(range was 4–12) and sex‐matched control patients with healthy fractures. Serum leptin and sOB‐R levels were quantified with ELISA. The free leptin index (FLI) was defined as the ratio of leptin to sOB‐R levels. Serum leptin levels, sOB‐R, and FLI were compared between groups. The relationship between leptin, disease severity, and treatment outcomes were analyzed in the LCPD group. There were no significant differences between groups in terms of age, sex, and body mass index (BMI) percentile. Mean leptin levels (p = 0.042), sOB‐R levels (p = 0.003), and FLI (p = 0.013) differed significantly between groups. In the LCPD group, the serum leptin levels, sOB‐R levels, and FLI differed significantly between the lateral pillar and Stulberg classification groups (p < 0.05). Also, the leptin levels and FLI increased significantly according to the lateral pillar and Stulberg classifications even after adjusting for age and BMI percentile (p < 0.05). Circulating leptin and FLI were significantly higher in the LCPD group. Furthermore, leptin, disease severity, and treatment outcomes were associated. This correlation suggests that leptin might play an important role in LCPD pathogenesis. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31:1605‐1610, 2013