Macrophage colony-stimulating factor (CSF-1) is a key regulatory cytokine for amelogenesis, and ameloblasts synthesize CSF-1. We hypothesized that PDGF stimulates DNA synthesis and regulates CSF-1 in these cells. We determined the effect of PDGF on CSF-1 expression using MEOE-3M ameloblasts as a model. By RT-PCR, MEOE-3M expressed PDGFRs and PDGF A- and B-chain mRNAs. PDGF-BB increased DNA synthesis and up-regulated CSF-1 mRNA and protein in MEOE-3M. Cells transfected with CSF-1 promoter deletion constructs were analyzed. A PDGF-responsive region between -1.7 and -0.795 kb, containing a consensus Pea3 binding motif, was identified. Electrophoretic mobility shift assay (EMSA) showed that PDGF-BB stimulated protein binding to this motif that was inhibited in the presence of anti-Pea3 antibody. Analysis of these data provides the first evidence that PDGF-BB is a mitogen for MEOE-3M and increases CSF-1 protein levels, predominantly by transcription. Elucidation of the cellular pathways that control CSF-1 expression may provide novel strategies for the regulation of enamel matrix formation.
[Show abstract][Hide abstract] ABSTRACT: Insulin-dependent type 1 diabetes mellitus (DM) and oral diseases are closely interrelated. Poor metabolic control in diabetics is associated with a high risk of gingivitis, periodontitis and tooth loss. Salivary flow declines in diabetics and patients suffer from xerostomia. Reduced saliva predisposes to enamel hypomineralization and caries formation; however, the mechanisms that initiate and lead to progression of tooth decay and periodontitis in type 1 DM have not been explored. To address this issue, we analyzed tooth morphology in Akita ⁻/⁻ mice that harbor a point mutation in the Ins2 insulin gene, which leads to progressive hyperglycemia. Mandibles from Akita ⁻/⁻ and wild-type littermates were analyzed by microCT, scanning EM and histology; teeth were examined for amelogenin (Amel) and ameloblastin (Ambn) expression. Mice were injected with pilocarpine to assess saliva production. As hyperglycemia may alter pulp repair, the effect of high glucose levels on the proliferation/differentiation of cultured MD10-F2 pulp cells was also analyzed. Results showed that Akita ⁻/⁻ mice at 6 weeks of age showed chalky white incisors that correlated with marked hyperglycemia and impaired saliva production. MicroCT of Akita ⁻/⁻ teeth revealed excessive enamel wearing and hypomineralization; immunostaining for Amel and Ambn was decreased. A striking feature was invasion of dentinal tubules with Streptococcus mitis and microabcesses that originated in the coronal pulp and progressed to pulp necrosis and periapical periodontitis. High levels of glucose also inhibited MD10-F2 cell proliferation and differentiation. Our findings provide the first evidence that hyperglycemia in combination with reduced saliva in a model of type1 DM leads to decreased enamel mineralization/matrix proteins and predisposes to excessive wearing and decay. Importantly, hyperglycemia adversely affects enamel matrix proteins and pulp repair. Early detection and treatment of hyperglycemia and hyposalivation may provide a useful strategy for preventing the dental complications of diabetes and promoting oral health in this population.
[Show abstract][Hide abstract] ABSTRACT: Radiotherapy is a major frontline treatment for prostate cancer patients, yet, a large portion of these patients suffer from local tumor recurrence. Tumor-infiltrating myeloid cells (TIMs), including CD11b+F4/80+ tumor-associated macrophages (TAMs) and CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs), play critical roles in promoting tumor angiogenesis, tissue remodeling and immunosuppression. Here, we show enhanced recruitment of TAMs and MDSCs after local irradiation. Although treatment is directed to the tumor sites, the impact of irradiation is systemic as dramatic increases of MDSCs were observed in the spleen, lung, lymph nodes and peripheral blood. Of the cytokines examined, we found that macrophage colony-stimulating factor 1 (CSF1) increased by 2 fold in irradiated tumors. Enhanced macrophage migration induced by conditioned media from irradiated tumor cells was completely blocked by the selective CSF1R inhibitor, GW2580. Importantly, increased CSF1 levels were also observed in the serum of prostate cancer patients after radiotherapy. ABL1 (c-Abl), a non-receptor tyrosine kinase, known to mediate apoptosis and signal transduction under stress, is activated by irradiation. Activated ABL1 translocates to the nucleus, binds to the CSF1 promoter region and enhances CSF1 transcription. Combination therapy using a CSF1R inhibitor currently in clinical trials, PLX3397, with radiation suppressed tumor growth more effectively than radiation alone. This study highlights the importance of CSF1/CSF1R signaling in the recruitment of TIMs in response to radiotherapy and suggests their significant role in promoting tumor recurrence. Furthermore, our data supports co-targeting TIMs in conjunction with radiotherapy to achieve a more effective and durable treatment strategy for prostate cancer patients.
Cancer Research 02/2013; 73(9). DOI:10.1158/0008-5472.CAN-12-3981 · 9.33 Impact Factor
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