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Osteoporosis is a common debilitating chronic disease diagnosed primarily using bone mineral density (BMD). We undertook a comprehensive assessment of human genetic determinants of bone density in 426,824 individuals, identifying a total of 518 genome-wide significant loci, (301 novel), explaining 20% of the total variance in BMD—as estimated by heel quantitative ultrasound (eBMD). Next, meta-analysis identified 13 bone fracture loci in ~1.2M individuals, which were also associated with BMD. We then identified target genes from cell-specific genomic landscape features, including chromatin conformation and accessible chromatin sites, that were strongly enriched for genes known to influence bone density and strength (maximum odds ratio = 58, P = 10-75). We next performed rapid throughput skeletal phenotyping of 126 knockout mice lacking eBMD Target Genes and showed that these mice had an increased frequency of abnormal skeletal phenotypes compared to 526 unselected lines (P < 0.0001). In-depth analysis of one such Target Gene, DAAM2, showed a disproportionate decrease in bone strength relative to mineralization. This comprehensive human and murine genetic atlas provides empirical evidence testing how to link associated SNPs to causal genes, offers new insights into osteoporosis pathophysiology and highlights opportunities for drug development.

While genetically engineered mice have made an enormous contribution towards the elucidation of human disease, it has hitherto not been possible to tune up or down the level of expression of any endogenous gene. Here we describe compound genetically modified mice in which expression of the endogenous E2f3 gene may be either reversibly elevated or repressed in adult animals by oral administration of tetracycline. This technology is, in principle, applicable to any endogenous gene, allowing direct determination of both elevated and reduced gene expression in physiological and pathological processes. Applying this switchable technology to the key cell cycle transcription factor E2F3, we demonstrate that elevated levels of E2F3 drive ectopic proliferation in multiple tissues. By contrast, E2F3 repression has minimal impact on tissue proliferation or homeostasis in the majority of contexts due to redundancy of adult function with E2F1 and E2F2. In the absence of E2F1 and E2F2, however, repression of E2F3 elicits profound reduction of proliferation in the hematopoietic compartments that is rapidly lethal in adult animals.

Thirty people with classical or definite rheumatoid arthritis received laser exposure to a Q-switch neodymium laser that operated at 1.06 micrometer with an output of 15 joules/cm2 for 30 nsec. One hand was lased at the proximal interphalangeal (PIP) and metacarpal phalangeal (MCP) joints, whereas the other hand was sham lased. The patient, physician, and occupational therapy evaluators did not know which hand was being lased. Twenty-one patients noted improvement of both their MCP and PIP joints of both hands during laser therapy. Twenty-seven noted improvement of their PIP joints and 26 noted improvement of the MCP joints during therapy. Heat, erythema, pain, swelling, and tenderness all improved with time in both hands, but the lased hand had more significant improvement in erythema and pain. There was also significant improvement in grasp and tip pressure on the lased side. The level of circulating immune complexes as measured by platelet aggregation decreased during lasing. The improvement may be related to laser exposure. The exact role that laser radiation has upon rheumatoid arthritis and its mechanism of action remain to be elucidated.

SummaryThe action of methandrostenolone on phenylbutazone and its major metabolite, oxyphenbutazone, has been studied in man by determining the half-life and plateau plasma levels of the antirheumatic drugs. The anabolic steroid caused an increase in the plasma level of oxyphenbutazone, confirming previous studies. This effect was previously attributed to a change in volume of distribution. In the present study, in addition to the effect on volume of distribution, a prolongation of half-life of oxyphenbutazone was observed in one subject. In contrast, in six patients receiving continuous therapy with phenylbutazone, plasma levels were unchanged when methandrostenolone was superimposed. The plasma levels of oxyphenbutazone, determined in the same samples, were unaffected. The half-life of phenylbutazone in two patients was not changed upon the administration of methandrostenolone, showing that no alteration had occurred in the metabolism of phenylbutazone. Equilibrium dialysis experiments indicated competi...

Clinical assessment (disease activity, severity, and extraarticular manifestations) of 101 rheumatoid arthritis patients was correlated with several laboratory tests, including 5 immune complex assays: the bovine conglutinin, 125I–C1q binding, monoclonal rheumatoid factor inhibition, Raji cell, and staphylococci binding assays. Elevated disease activity indices were most closely associated with the presence of immune complexes detected by the 125I–C1q and staphylococci binding assays. There were significant but weak correlations between the level of disease activity and the level of immune complexes as measured by the bovine conglutinin, 125I–C1q binding, Raji cell, and staphylococci binding assays. Articular disease severity, as measured by anatomic stage, was best discriminated by the bovine conglutinin, monoclonal rheumatoid factor inhibition, and staphylococci binding assays. Extraarticular manifestations were best discriminated by the Raji cell and staphylococci binding assays. We concluded that the sensitivity, specificity, predictive value, and overlap of the associations were not sufficient to warrant their wide use for the diagnosis and management of rheumatoid arthritis in individual patients. Conversely, the 125I–C1q and staphylococci binding assays were as good as the erythrocyte sedimentation rate and the IgG rheumatoid factor test (the 2 best tests of many examined) in assessing disease activity. Further prospective studies with these assays will determine their usefulness in following rheumatoid arthritis for a prolonged period.

Caspase-2 has been implicated in various cellular functions, including cell death by apoptosis, oxidative stress response, maintenance of genomic stability and tumor suppression. The loss of the caspase-2 gene (Casp2) enhances oncogene-mediated tumorigenesis induced by E1A/Ras in athymic nude mice, and also in the El-Myc lymphoma and MMTV/c-neu mammary tumor mouse models. To further investigate the function of caspase-2 in oncogene-mediated tumorigenesis, we extended our studies in the TH-MYCN transgenic mouse model of neuroblastoma. Surprisingly, we found that loss of caspase-2 delayed tumorigenesis in the TH-MYCN neuroblastoma model. In addition, tumors from TH-MYCN/Casp2 +/+ mice were predominantly thoracic paraspinal tumors and were less vascularized compared with tumors from their TH-MYCN/Casp2þ/þ counterparts. We did not detect any differences in the expression of neuroblastoma-associated genes in TH-MYCN/Casp2 / tumors, or in the activation of Ras/MAPK signaling pathway that is involved in neuroblastoma progression. Analysis of expression array data from human neuroblastoma samples showed a correlation between low caspase-2 levels and increased survival. However, caspase-2 levels correlated with clinical outcome only in the subset of MYCN-non-amplified human neuroblastoma. These observations indicate that caspase-2 is not a suppressor in MYCN-induced neuroblastoma and suggest a tissue and context-specific role for caspase-2 in tumorigenesis. Refereed/Peer-reviewed