Effective osteoporosis therapy requires agents that increase the amount and/or quality of bone. Any modification of osteoclast-mediated bone resorption by disease or drug treatment, however, elicits a parallel change in osteoblast-mediated bone formation because the processes are tightly coupled. Anabolic approaches now focus on uncoupling osteoblast action from osteoclast formation, for example, by inhibiting sclerostin, an inhibitor of bone formation that does not influence osteoclast differentiation. Here, we report that oncostatin M (OSM) is produced by osteoblasts and osteocytes in mouse bone and that it has distinct effects when acting through 2 different receptors, OSM receptor (OSMR) and leukemia inhibitory factor receptor (LIFR). Specifically, mouse OSM (mOSM) inhibited sclerostin production in a stromal cell line and in primary murine osteoblast cultures by acting through LIFR. In contrast, when acting through OSMR, mOSM stimulated RANKL production and osteoclast formation. A key role for OSMR in bone turnover was confirmed by the osteopetrotic phenotype of mice lacking OSMR. Furthermore, in contrast to the accepted model, in which mOSM acts only through OSMR, mOSM inhibited sclerostin expression in Osmr -/-osteoblasts and enhanced bone formation in vivo. These data reveal what we believe to be a novel pathway by which bone formation can be stimulated independently of bone resorption and provide new insights into OSMR and LIFR signaling that are relevant to other medical conditions, including cardiovascular and neurodegenerative diseases and cancer.

Osteoblasts and adipocytes are derived from common mesenchymal progenitor cells. The bone loss of osteoporosis is associated with altered progenitor differentiation from an osteoblastic to an adipocytic lineage. cDNA microarrays and quantitative real-time PCR (Q-PCR) were carried out in a differentiating mouse stromal osteoblastic cell line, Kusa 4b10, to identify gene targets of factors that stimulate osteoblast differentiation including parathyroid hormone (PTH) and gp130-binding cytokines, oncostatin M (OSM) and cardiotrophin-1 (CT-1). Zinc finger protein 467 (Zfp467) was rapidly downregulated by PTH, OSM, and CT-1. Retroviral overexpression and RNA interference for Zfp467 in mouse stromal cells showed that this factor stimulated adipocyte formation and inhibited osteoblast commitment compared with controls. Regulation of adipocyte markers, including peroxisome proliferator-activated receptor (PPAR) ␥, C/EBP␣, adiponectin, and resistin, and late osteoblast/osteocyte markers (osteocalcin and sclerostin) by Zfp467 was confirmed by Q-PCR. Intra-tibial injection of calvarial cells transduced with retroviral Zfp467 doubled the number of marrow adipocytes in C57Bl/6 mice compared with vector control-transduced cells, providing in vivo confirmation of a pro-adipogenic role of Zfp467. Furthermore, Zfp467 transactivated a PPAR-response element reporter construct and recruited a histone deacetylase complex. Thus Zfp467 is a novel co-factor that promotes adipocyte differentiation and suppresses osteoblast differentiation. This has relevance to therapeutic interventions in osteoporosis, including PTH-based therapies currently available, and may be of relevance for the use of adipose-derived stem cells for tissue engineering.Osteoblasts and adipocytes are derived from a common subpopulation of mesenchymal stem cell (MSC) 4 progenitors.MSC lineage commitment is dependent on the expression of key transcription factors that, on induction, initiate a cascade of events culminating in cellular differentiation and development. Among the transcription factors regulated, osteoblast differentiation requires expression of Runx2 (1, 2) to commit progenitors to preosteoblasts, with Osterix (3), ATF4 (4), and AP-1 (5) promoting their transition to functional osteoblasts. Alternately, adipocytic differentiation requires expression of different key regulators, peroxisome proliferator-activated receptor ␥ (PPAR␥) (6) and members of the CCAAT/enhancer-binding protein family (C/EBPs) (7). Because osteoblasts and adipocytes are derived from common progenitors, lineage determination of precursor cells to osteoblasts results in a proportional decrease in adipogenesis. This inverse relationship is observed clinically; an increase in marrow adiposity is associated with age-related osteoporosis (8) and conditions that induce bone loss, such as ovariectomy (9) and immobilization (10). Conversely, high bone mass due to increased osteoblast commitment is associated with reduced adipocyte differentiation (5). The molecular mechanisms by which lineage...

Brazil is the world largest pesticide consumer; therefore, it is important to monitor the levels of these chemicals in the water used by population. The Ministry of Health coordinates the National Drinking Water Quality Surveillance Program (Vigiagua) with the objective to monitor water quality. Water quality data are introduced in the program by state and municipal health secretariats using a database called Sisagua (Information System of Water Quality Monitoring). Brazilian drinking water norm (Ordinance 2914/2011 from Ministry of Health) includes 27 pesticide active ingredients that need to be monitored every 6 months. This number represents <10% of current active ingredients approved for use in the country. In this work, we analyzed data compiled in Sisagua database in a qualitative and quantitative way. From 2007 to 2010, approximately 169,000 pesticide analytical results were prepared and evaluated, although approximately 980,000 would be expected if all municipalities registered their analyses. This shows that only 9–17% of municipalities registered their data in Sisagua. In this dataset, we observed non-compliance with the minimum sampling number required by the norm, lack of information about detection and quantification limits, insufficient standardization in expression of results, and several inconsistencies, leading to low credibility of pesticide data provided by the system. Therefore, it is not possible to evaluate exposure of total Brazilian population to pesticides via drinking water using the current national database system Sisagua. Lessons learned from this study could provide insights into the monitoring and reporting of pesticide residues in drinking water worldwide.

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