Disruption of PTH Receptor 1 in T Cells Protects against PTH-Induced Bone Loss

Hyperparathyroidism in humans and continuous parathyroid hormone (cPTH) treatment in mice cause bone loss by regulating the production of RANKL and OPG by stromal cells (SCs) and osteoblasts (OBs). Recently, it has been reported that T cells are required for cPTH to induce bone loss as the binding of the T cell costimulatory molecule CD40L to SC receptor CD40 augments SC sensitivity to cPTH. However it is unknown whether direct PTH stimulation of T cells is required for cPTH to induce bone loss, and whether T cells contribute to the bone catabolic activity of PTH with mechanisms other than induction of CD40 signaling in SCs.Here we show that silencing of PTH receptor 1 (PPR) in T cells blocks the bone loss and the osteoclastic expansion induced by cPTH, thus demonstrating that PPR signaling in T cells is central for PTH-induced reduction of bone mass. Mechanistic studies revealed that PTH activation of the T cell PPR stimulates T cell production of the osteoclastogenic cytokine tumor necrosis factor alpha (TNF). Attesting to the relevance of this effect, disruption of T cell TNF production prevents PTH-induced bone loss. We also show that a novel mechanism by which TNF mediates PTH induced osteoclast formation is upregulation of CD40 expression in SCs, which increases their RANKL/OPG production ratio.These findings demonstrate that PPR signaling in T cells plays an essential role in PTH induced bone loss by promoting T cell production of TNF. A previously unknown effect of TNF is to increase SC expression of CD40, which in turn increases SC osteoclastogenic activity by upregulating their RANKL/OPG production ratio. PPR-dependent stimulation of TNF production by T cells and the resulting TNF regulation of CD40 signaling in SCs are potential new therapeutic targets for the bone loss of hyperparathyroidism

Operons

Operons (clusters of co-regulated genes with related functions) are common features of bacterial genomes. More recently, functional gene clustering has been reported in eukaryotes, from yeasts to filamentous fungi, plants, and animals. Gene clusters can consist of paralogous genes that have most likely arisen by gene duplication. However, there are now many examples of eukaryotic gene clusters that contain functionally related but non-homologous genes and that represent functional gene organizations with operon-like features (physical clustering and co-regulation). These include gene clusters for use of different carbon and nitrogen sources in yeasts, for production of antibiotics, toxins, and virulence determinants in filamentous fungi, for production of defense compounds in plants, and for innate and adaptive immunity in animals (the major histocompatibility locus). The aim of this article is to review features of functional gene clusters in prokaryotes and eukaryotes and the significance of clustering for effective function

Women’s Perceptions of Their Community’s Social Norms Towards Assisting Women Who Have Experienced Intimate Partner Violence

The role of social norms has played an often unrecognized role in the perception of and action to assist low-income urban women who are in violent relationships. Two forms of social norms will be assessed, including descriptive norms—what people typically do to assist women in a violent relationship—and injunctive norms—defined as what people should do to assist women. This study will present our initial findings into the development of measures to assess women’s perception of their community’s social norms toward assisting women who have experienced intimate partner violence (IPV) and how these norms are related to women’s perception of the community, reasons for community assistance toward women experiencing IPV, and women’s own experience of IPV. Systematic measurement development processes were applied to reliably and validly develop the social norms measures. A three-phase approach was used to develop eight paired items measuring descriptive and injunctive norms. A total of 176 low-income urban women were interviewed and the scale responses were compared to length of time at the residence, perceptions of their neighborhood, perceived reasons for community involvement and non-involvement in assisting women experiencing IPV, and IPV experienced as an adult. The two developed social norms scales were found to have high internal consistency alpha coefficients of 0.84 for descriptive norms and 0.93 for injunctive norms. Paired t tests were statistically significant, denoting higher injunctive than descriptive social norms. Lowered descriptive norms were found among younger women, women who reported that they did not think their neighborhood was a good place to live, women who had ever experienced intimate partner violence as an adult, and perceived lower reasons for neighbor involvement and higher reasons for neighbor non-involvement toward assisting women experiencing IPV. Higher levels of injunctive social norms were statistically associated with living in a good place and increased perceived reasons for neighbor involvement toward assisting women experiencing IPV. Significant differences between descriptive and injunctive norms suggest that women, especially those who are currently experiencing IPV, would prefer greater support from community neighbors than they are currently providing. The descriptive and injunctive social norms scales demonstrated a high level of internal reliability and significantly associated with other influencing factors thought to be associated with social norms. Overall, the performance of the injunctive and descriptive norms scales support their use as a tool to investigate social norms toward neighbors taking action to assist women experiencing IPV