Conditional Loss of Nmp4 in Mesenchymal Stem Progenitor Cells Enhances PTH-Induced Bone Formation

Activation of bone anabolic pathways is a fruitful approach for treating severe osteoporosis. Yet, FDA-approved osteoanabolics, e.g., parathyroid hormone (PTH), have limited efficacy. Improving their potency is a promising strategy for maximizing bone anabolic output. Nmp4 (Nuclear Matrix Protein 4) global knockout mice, exhibit enhanced PTH-induced increases in trabecular bone but display no overt baseline skeletal phenotype. Nmp4 is expressed in all tissues; therefore, to determine which cell type is responsible for driving the beneficial effects of Nmp4 inhibition, we conditionally removed this gene from cells at distinct stages of osteogenic differentiation. Nmp4-floxed (Nmp4fl/fl) mice were crossed with mice bearing one of three Cre drivers including (i) Prx1Cre+ to remove Nmp4 from mesenchymal stem/progenitor cells (MSPCs) in long bones; (ii) BglapCre+ targeting mature osteoblasts and (iii) Dmp1Cre+ to disable Nmp4 in osteocytes. Virgin female Cre+ and Cre− mice (10wks of age) were sorted into cohorts by weight and genotype. Mice were administered daily injections of either human PTH 1–34 at 30μg/kg, or vehicle for 4wks or 7wks. Skeletal response was assessed using dual-energy X-ray absorptiometry, microcomputed tomography, bone histomorphometry and serum analysis for remodeling markers. Nmp4fl/fl;Prx1Cre+ mice virtually phenocopied the global Nmp4−/− skeleton in the femur, i.e., a mild baseline phenotype but significantly enhanced PTH-induced increase in femur trabecular bone volume/total volume (BV/TV) compared to their Nmp4fl/fl;Prx1Cre− controls. This was not observed in the spine, where Prrx1 is not expressed. Heightened response to PTH was coincident with enhanced bone formation. Conditional loss of Nmp4 from the mature osteoblasts (Nmp4fl/fl;BglapCre+) failed to increase BV/TV or enhance PTH response. However, conditional disabling of Nmp4 in osteocytes (Nmp4fl/fl;Dmp1Cre+) increased BV/TV without boosting response to hormone under our experimental regimen. We conclude that Nmp4−/− Prx1-expressing MSPCs drive the improved response to PTH therapy, and that this gene has stage-specific effects on osteoanabolism

NMP4, An Arbiter of Bone Cell Secretory Capacity And Regulator of Skeletal Response to PTH Therapy

The skeleton is a secretory organ, and the goal of some osteoporosis therapies is to maximize bone matrix output. Nmp4 encodes a novel transcription factor that regulates bone cell secretion as part of its functional repertoire. Loss of Nmp4 enhances bone response to osteoanabolic therapy, in part, by increasing the production and delivery of bone matrix. Nmp4 shares traits with scaling factors, which are transcription factors that influence the expression of hundreds of genes to govern proteome allocation for establishing secretory cell infrastructure and capacity. Nmp4 is expressed in all tissues and while global loss of this gene leads to no overt baseline phenotype, deletion of Nmp4 has broad tissue effects in mice challenged with certain stressors. In addition to an enhanced response to osteoporosis therapies, Nmp4-deficient mice are less sensitive to high fat diet-induced weight gain and insulin resistance, exhibit a reduced disease severity in response to influenza A virus (IAV) infection, and resist the development of some forms of rheumatoid arthritis. In this review, we present the current understanding of the mechanisms underlying Nmp4 regulation of the skeletal response to osteoanabolics, and we discuss how this unique gene contributes to the diverse phenotypes among different tissues and stresses. An emerging theme is that Nmp4 is important for the infrastructure and capacity of secretory cells that are critical for health and disease

Self-Reported Comorbid Pains in Severe Headaches or Migraines in a US National Sample

AIMS: To compare prevalence of self-reported comorbid temporomandibular joint muscle disorder (TMJMD)-type, neck, back and joint pains in people with severe headache or migraine; analyze these self-reported pains in the 2000–2005 US National Health Interview Survey (NHIS) by gender and age for Non-Hispanic Whites, Hispanics and Non-Hispanic Blacks (African Americans). METHODS: NHIS data included information on gender, age, race, ethnicity, health status, and common pain types: severe headache or migraine, TMJMD-type, neck, and low back in the last 3 months, as well as prior month joint pains. Analyses included survey prevalence estimation and survey logistic regression to obtain odds ratios and 95% confidence intervals. RESULTS: 189,967 adults, 48% males, 52% females; 73% White, 12% Hispanic, and 11% Black were included. 29,712 (15%) of the entire sample reported severe headache or migraine, 19,228 (64%) had severe headache or migraine with at least one comorbid pain. 10,200 (33%) reported 2 or more comorbid pains, with no gender difference, and with Hispanics (n=1,847 or 32%) and Blacks (n=1,301 or 30%) less likely to report 2 or more comorbid pains than Whites (n=6,747 or 34%) (OR=0.91, p=0.032; OR=0.82, p<0.001, respectively). This group also reported significantly lower ratings of self-rated health (p<0.001). Differences in type of comorbid pain by age patterns were found. CONCLUSIONS: Severe headache or migraine is often associated with other common pains, seldom existing alone. Two or more comorbid pains are common, similarly affecting gender and racial/ethnic groups

Antidepressant Treatment and Health Services Utilization Among HIV-Infected Medicaid Patients Diagnosed with Depression

OBJECTIVE: To characterize the prevalence and predictors of diagnosed depression among persons with HIV on Medicaid and antidepressant treatment among those diagnosed, and to compare utilization and costs between depressed HIV-infected individuals treated with and without antidepressant medications. DESIGN: Merged Medicaid and surveillance data were used to compare health services utilized by depressed individuals who were or were not treated with antidepressant medications, controlling for other characteristics. SETTING AND PARTICIPANTS: The study population comprised Medicaid recipients in New Jersey who were diagnosed with HIV or AIDS by March 1996 and received Medicaid services between 1991 and 1996. MEASUREMENTS AND MAIN RESULTS: Logistic regression and ordinary least squares regressions were employed. Women were more likely and African Americans were less likely to be diagnosed with depression. Women and drug users in treatment were more likely to receive antidepressant treatment. Depressed patients treated with antidepressants were more likely to receive antiretroviral treatment than those not treated with antidepressants. Monthly total expenditures were significantly lower for individuals diagnosed with depression and receiving antidepressant therapy than for those not treated with antidepressants. After controlling for socioeconomic and clinical characteristics, treatment with antidepressant medications was associated with a 24% reduction in monthly total health care costs. CONCLUSIONS: Depressed HIV-infected patients treated with antidepressants were more likely than untreated subjects to receive appropriate care for their HIV disease. Antidepressant therapy for treatment of depression is associated with a significantly lower monthly cost of medical care services