Osteoarthritis (OA) is a degenerative joint disease, and the mechanism of its pathogenesis is poorly understood. Recent human genetic association studies showed that mutations in the Frzb gene predispose patients to OA, suggesting that the Wnt/-catenin signaling may be the key pathway to the development of OA. However, direct genetic evidence for -catenin in this disease has not been reported. Because tissue-specific activation of the -catenin gene (targeted by Col2a1-Cre) is embryonic lethal, we specifically activated the -catenin gene in articular chondrocytes in adult mice by generating -catenin conditional activation (cAct) mice through breeding of -catenin fx(Ex3)/fx(Ex3) mice with Col2a1-CreER T2 transgenic mice. Deletion of exon 3 of the -catenin gene results in the production of a stabilized fusion -catenin protein that is resistant to phosphorylation by GSK-3. In this study, tamoxifen was administered to the 3-and 6-mo-old Col2a1-CreER T2 ;-catenin fx(Ex3)/wt mice, and tissues were harvested for histologic analysis 2 mo after tamoxifen induction. Overexpression of -catenin protein was detected by immunostaining in articular cartilage tissues of -catenin cAct mice. In 5-mo-old -catenin cAct mice, reduction of Safranin O and Alcian blue staining in articular cartilage tissue and reduced articular cartilage area were observed. In 8-mo-old -catenin cAct mice, cell cloning, surface fibrillation, vertical clefting, and chondrophyte/osteophyte formation were observed. Complete loss of articular cartilage layers and the formation of new woven bone in the subchondral bone area were also found in -catenin cAct mice. Expression of chondrocyte marker genes, such as aggrecan, Mmp-9, Mmp-13, Alp, Oc, and colX, was significantly increased (3-to 6-fold) in articular chondrocytes derived from -catenin cAct mice. Bmp2 but not Bmp4 expression was also significantly upregulated (6-fold increase) in these cells. In addition, we also observed overexpression of -catenin protein in the knee joint samples from patients with OA. These findings indicate that activation of -catenin signaling in articular chondrocytes in adult mice leads to the premature chondrocyte differentiation and the development of an OA-like phenotype. This study provides direct and definitive evidence about the role of -catenin in the development of OA.
Objective The incidence of low back pain is extremely high and is often linked to intervertebral disc (IVD) degeneration. The mechanism of this disease is currently unknown. In this study, we have investigated the role of β-catenin signaling in IVD tissue function. Methods β-catenin protein levels were measured in disc samples derived from patients with disc degeneration and normal subjects by immunohistochemistry (IHC). To generate β-catenin conditional activation (cAct) mice, Col2a1-CreERT2 transgenic mice were bred with β-cateninfx(Ex3)/fx(Ex3) mice. Changes in disc tissue morphology and function were analyzed by micro-CT, histology and real-time PCR assays. Results We found that β-catenin protein was up-regulated in disc tissues from patients with disc degeneration. To assess the effects of increased β-catenin on disc tissue we generated β-catenin cAct mice. Overexpression of β-catenin in disc cells led to extensive osteophyte formation in 3- and 6-month-old β-catenin cAct mice which were associated with significant changes in the cells and extracellular matrix of disc tissues and growth plate. Gene expression analysis demonstrated that activation of β-catenin could enhance Runx2-dependent Mmp13 and Adamts5 expression. Moreover, genetic ablation of the Mmp13 or Adamts5 under β-catenin cAct background, or treatment of β-catenin cAct mice with a specific MMP13 inhibitor, ameliorated the mutant phenotype. Conclusions β-catenin signaling pathway plays a critical role in disc tissue function.
Of 92 patients with lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) treated at our institution, diffuse large B-cell lymphoma (DLBCL) also developed in 12 (13%). In 10 patients, DLBCL developed 12 to 128 months (median, 44 months) after the diagnosis of LPL/WM. Two patients had LPL/WM and DLBCL simultaneously. Clinicopathologic features at diagnosis of LPL/WM did not predict the risk of DLBCL. Onset of DLBCL was characterized by worsening constitutional symptoms, profound cytopenias, extramedullary disease, and organomegaly. Immunoglobulin light chain expression was identical in both LPL/WM and DLBCL. In situ hybridization for Epstein-Barr virus (EBV) in 8 cases of DLBCL was negative. Of 11 patients with clinical follow-up information available, 8 (73%) died within 10 months of diagnosis of DLBCL. DLBCL, most likely as a result of histologic transformation, occurs in a subset of patients with LPL/WM and is associated with aggressive clinical course and poor outcome. EBV is unlikely to be involved in transformation.
The E3 ubiquitin ligase Smurf2 mediates ubiquitination and degradation of several protein targets involved in tumorigenesis and induces senescence in human cells. However, the functional role of Smurf2 in tumorigenesis has not been fully evaluated. In this study, we generated a mouse model of Smurf2 deficiency to characterize the function of this E3 ligase in tumorigenesis. Smurf2 deficiency attenuated p16 expression and impaired the senescence response of primary mouse embryonic fibroblasts. In support of a functional role in controlling cancer, Smurf2 deficiency increased the susceptibility of mice to spontaneous tumorigenesis, most notably B cell lymphoma. At a premalignant stage of tumorigenesis, we documented a defective senescence response in the spleens of Smurf2-deficient mice, consistent with a mechanistic link between impaired senescence regulation and increased tumorigenesis. Taken together, our findings offer the genetic evidence of an important tumor suppressor function for Smurf2.
The t(11;14)(q13;q32) resulting in cyclin D1 overexpression is consistently present in mantle cell lymphoma. However secondary chromosomal aberrations are also extremely common. Of these, 8q24 abnormalities associated with the t(11;14) are rare. Over the course of 10 years at M.D. Anderson Cancer Center, we identified five cases of mantle cell lymphoma in which conventional cytogenetic analysis revealed complex karyotypes, including the t(11;14) and 8q24 abnormalities: one with t(8;14)(q24;q32), one with t(2;8)(q13; q24), and three with add(8)(q24). We performed fluorescence in situ hybridization (FISH) studies on all cases. In the case with the t(8;14), IgH/myc fusion signals were identified, and in the case with the t(2;8), split c-myc signals were detected. In the three cases with add(8)(q24), one case had split c-myc signals and two cases had three copies of c-myc. Thus, the c-myc gene was involved in all cases. All five neoplasms had blastoid morphologic features, and four cases, including the cases with the t(8; 14) and t(2;8), had leukemic involvement. We conclude that 8q24 abnormalities involving the c-myc gene are uncommon secondary abnormalities that occur in a subset of mantle cell lymphomas. C-myc gene abnormalities are associated with blastoid cytologic features and also may be associated with leukemic involvement.
We identified 382 consecutive patients with lymphoid neoplasms associated with serum monoclonal IgM paraprotein and classified each neoplasm according to World Health Organization criteria. Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) was most common, 225 cases (median serum IgM level, 2.2 g/dL; range, 0.2-10.9 g/dL). For 157 cases, classification and median (and range in g/dL) IgM levels were as follows: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n = 77), 0.9 (0.1-2.1); marginal zone lymphoma (n = 27), 0.5 (0.1-2.4); follicular lymphoma (n = 18), 0.4 (0.1-1.6); mantle cell lymphoma (n = 11), 0.4 (0.2-1.3); diffuse large B-cell lymphoma (DLBCL; n = 7), 0.5 (0.2-1.0); DLBCL associated with low-grade lymphoma (n = 5), 0.9 (0.4-3.0); angioimmunoblastic T-cell lymphoma (n = 4), 0.8 (0.8); and CD5+CD23- low-grade B-cell lymphoma, unclassified (n = 8), 0.5 (0.3-2.9). The results show IgM paraproteinemia was associated most commonly with LPL/WM (58.9%), followed by CLL/SLL (20.2%). Although serum IgM levels greater than 3 g/dL were restricted to patients with LPL/WM, most patients with LPL/WM had paraprotein levels less than 3 g/dL. Thus, serum IgM paraprotein level is not a reliable discriminator in differential diagnosis.
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