This study demonstrates that BMD in healthy men is highly heritable with similar estimates of the genetic contribution to BMD in both whites and blacks. Of the six QTL identified, three were specific for spine BMD and three were specific for hip BMD. When compared with published QTL for peak BMD in women from the same geographical region, four of the QTL appeared to be male specific. The occurrence of sex-specific genes in humans for BMD has potentially important implications for the pathogenesis and treatment of osteoporosis.

Prostate is the most frequent cancer in men. Prostate cancer progression is driven by androgen steroid hormones, and delayed by androgen deprivation therapy (ADT). Androgens control transcription by stimulating androgen receptor (AR) activity, yet also control pre-mRNA splicing through less clear mechanisms. Here we find androgens regulate splicing through AR-mediated transcriptional control of the epithelial-specific splicing regulator ESRP2. Both ESRP2 and its close paralog ESRP1 are highly expressed in primary prostate cancer. Androgen stimulation induces splicing switches in many endogenous ESRP2-controlled mRNA isoforms, including splicing switches correlating with disease progression. ESRP2 expression in clinical prostate cancer is repressed by ADT, which may thus inadvertently dampen epithelial splice programmes. Supporting this, treatment with the AR antagonist bicalutamide (Casodex) induced mesenchymal splicing patterns of genes including FLNB and CTNND1. Our data reveals a new mechanism of splicing control in prostate cancer with important implications for disease progression.

No abstract

Intracellular signals involved in the maturation and function of osteoclasts are poorly understood. Here, we demonstrate that osteoclasts express multiple regulatory subunits of class I A phosphatidylinositol 3-kinase (PI3-K) although the expression of the full-length form of p85␣ is most abundant. In vivo, deficiency of p85␣ results in a significantly greater number of trabeculae and significantly lower spacing between trabeculae as well as increased bone mass in both males and females compared to their sex-matched wild-type controls. Consistently, p85␣؊/؊ osteoclast progenitors show impaired growth and differentiation, which is associated with reduced activation of Akt and mitogen-activated protein kinase extracellular signal-regulated kinase 1 (Erk1)/Erk2 in vitro. Furthermore, a significant reduction in the ability of p85␣ ؊/؊ osteoclasts to adhere to as well as to migrate via integrin ␣v␤3 was observed, which was associated with reduced bone resorption. Microarray as well as quantitative real-time PCR analysis of p85␣؊/؊ osteoclasts revealed a significant reduction in the expression of several genes associated with the maturation and migration of osteoclasts, including microphathalmia-associated transcription factor, tartrate-resistant acid phosphatase, cathepsin K, and ␤3 integrin. Restoring the expression of the full-length form of p85␣ but not the version with a deletion of the Src homology-3 domain restored the maturation of p85␣ ؊/؊ osteoclasts to wild-type levels. These results highlight the importance of the full-length version of the p85␣ subunit of class I A PI3-K in controlling multiple aspects of osteoclast functions.Osteoclasts (OCs) are derived from precursors of monocyte/ macrophage lineage, whose growth and maturation are mainly dependent on two osteoblast/stromal cell-derived cytokines, including macrophage colony stimulating factor (M-CSF) and receptor activator of NF-B ligand (RANKL) (22,30,35,63). The critical role for these two cytokines in OC growth and differentiation has been further illustrated by studying mice lacking the expression of 64). These mice show severe osteopetrosis and lack mature OCs. M-CSF and RANKL regulate OC progenitor (OCp) growth and function in part by regulating the expression of several OC genes, including tartrate-resistant acid phosphatase (TRAP), cathepsin K, calcitonin receptor, and integrin ␤3 (15, 29). Stimulation of OC precursors by RANKL and M-CSF results in the activation of a number of signaling molecules, including Gab2, Grb2, Vav, Src homology-2 (SH2)-containing inositol-5-

Osteoarthritis (OA) risk is widely recognized to be heritable but few loci have been identified. Observational studies have identified higher systemic bone mineral density (BMD) to be associated with an increased risk of radiographic knee osteoarthritis. With this in mind, we sought to evaluate whether well-established genetic loci for variance in BMD are associated with risk for radiographic OA in the Osteoarthritis Initiative (OAI) and the Johnston County Osteoarthritis (JoCo) Project. Cases had at least one knee with definite radiographic OA defined as the presence of definite osteophytes with or without joint space narrowing (KL grade ≥ 2) and controls were absent for definite radiographic OA in both knees (KL grade ≤ 1bilaterally). There were 2014 and 658 Caucasian cases, respectively, in the OAI and JoCo Studies, and 953 and 823 controls. Single nucleotide polymorphisms (SNPs) were identified for association analysis from the literature. Genotyping was carried out on the Illumina 2.5M and 1M arrays in GeCKO and JoCo, respectively and imputation was done. Association analyses were carried out separately in each cohort with adjustments for age, BMI, and sex and then parameter estimates were combined across the two cohorts by meta-analysis. We identified 4 SNPs significantly associated with prevalent radiographic knee OA. The strongest signal (p=0.0009, OR=1.22, 95% CI[1.08–1.37]) maps to 12q3 which contains a gene coding for SP7. Additional loci map to 7p14.1 (TXNDC3), 11q13.2 (LRP5) and 11p14.1 (LIN7C). For all four loci the allele associated with higher BMD was associated with higher odds of OA. A BMD risk allele score was not significantly associated with OA risk. This meta-analysis demonstrates that several GWAS-identified BMD SNPs are nominally associated with prevalent radiographic knee OA and further supports the hypothesis that BMD, or its determinants, may be a risk factor contributing to OA development.

No abstract

To prevent and treat chronic diseases, including cancer, a global application of systems biology is needed. We report here a whole blood transcriptome test that needs only 50 μl of capillary (fingerprick) blood. This test is suitable for global applications because the samples are preserved at ambient temperature for up to 4 weeks and the RNA preservative inactivates all pathogens, enabling safe transportation. Both the laboratory and bioinformatic steps are automated and performed in a clinical lab, which minimizes batch effects and creates unbiased datasets. Given its clinical testing performance and accessibility to traditionally underrepresented and diverse populations, this test offers a unique ability to reveal molecular mechanisms of disease and enable longitudinal, population-scale studies.

We show that loss of p85␣ inhibits the growth and maturation of mast cells, whereas loss of p85␤ enhances this process. Whereas restoring the expression of p85␣ in P85␣ ؊/؊ cells restores these functions, overexpression of p85␤ has the opposite effect. Consistently, overexpression of p85␤ in WT mast cells represses KIT-induced proliferation and IL-3-mediated maturation by inhibiting the expression of Microphthalmia transcription factor. Because p85␣ and p85␤ differ in their N-terminal sequences, chimeric proteins consisting of amino or carboxy-terminal of p85␣ and/or p85␤ do not rescue the growth defects of p85␣ ؊/؊ cells, suggesting cooperation between these domains for normal mast cell function. Loss of p85␤ impaired ligand induced KIT receptor internalization and its overexpression enhanced this process, partly because of increased binding of c-Cbl to p85␤ relative to p85␣. In vivo, loss of p85␤ resulted in increased mast IntroductionMast cells are effector cells of the immune system that originate from multipotent stem cells in the bone marrow (BM). 1,2 These cells regulate both innate and adaptive immunity 3,4 and have been implicated in a variety of inflammatory diseases, including multiple sclerosis, atherosclerosis, rheumatoid arthritis, coronary artery disease, inflammatory bowel disease, and angiogenesis. 5 In the BM, growth and differentiation of mast cells are critically dependent on signals regulated by the KIT and IL-3 receptors. 6-12 KIT belongs to type 3 receptor tyrosine kinase subfamily and is encoded by the W locus. 13 Loss of function of KIT because of mutations at the W locus results in ablation of KIT tyrosine kinase activity, leading to defective mast cell growth and severe mast cell deficiency in all tissues. 14 Although normal KIT signaling is vital for various mast cell related functions, abnormal KIT signaling because of activating mutations in the KIT receptor have been described in germ cell tumors, 15 gastrointestinal stromal tumors, 16 lymphomas, 17 acute myeloid leukemia, 18 and systemic mastocytosis. 19 For some of these mutations, including the KITD816V mutation found in patients with acute myeloid leukemia and systemic mastocytosis, no good therapies are currently available.In addition to KIT and its ligand SCF, IL-3 is also critical for the development, survival, and function of tissue mast cells, 11,12 in particular under conditions of immunologic stress. 20 Although it is known for some time that KIT and IL-3 receptor-induced signals are essential for mast cell growth and differentiation, the nature of intracellular signals downstream from these receptors in regulating both growth and maturation of these cells is poorly understood. To this end, studies by Fukao et al have shown that some PI3 kinase (PI3K) signaling components may contribute to mast cell development. 21 PI3K is a lipid kinase composed of a heterodimer made up of p85 regulatory subunit(s) and p110 catalytic subunit(s). In hematopoietic cells, 4 regulatory (p85␣, p85␤, p55␣, and p50␣) and 3 catalytic (p110␣, p...