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.

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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.