Integrin adhesion receptors can act as signaling receptors that transmit information from the extracellular environment to the interior of the cell, affecting many fundamental cellular processes, such as cell motility, proliferation, differentiation, and survival. Integrin signaling depends on the formation of organized sub-membrane complexes that comprise cytoskeletal, adapter, and signaling molecules. The identification of molecules that interact with the cytoplasmic domain of integrins has been the focus of research aimed to elucidating the mechanistic basis of integrin signal transduction. We have identified RanBPM as a novel interactor of the ␤ 2 integrin LFA-1 in a yeast-two-hybrid screen. In the same assay, RanBPM also interacted with the ␤ 1 integrin cytoplasmic domain. We demonstrate that Ran-BPM is a peripheral membrane protein and that integrins and RanBPM interact in vitro and in vivo and co-localize at the cell membrane. We find that RanBPM is phosphorylated on serine residues; phosphorylation of RanBPM is increased by stress stimuli and decreased by treatment with the p38 kinase inhibitor SB203580. Transfection of RanBPM synergizes with LFA-1-mediated adhesion in the transcriptional activation of an AP-1-dependent promoter, indicating that the two proteins interact functionally as well. We suggest that RanBPM may constitute a molecular scaffold that contributes to coupling LFA-1 and other integrins with intracellular signaling pathways.

The objectives of the present study were to calculate the cost of illness of osteoporosis and to assess drug utilization patterns in postmenopausal women after a fracture-related hospitalization. The study subjects were enrolled from a large population-based administrative database. Female patients (age ≥ 65 years) who were hospitalized for a typical osteoporotic fracture between 1/1/2000 and 31/12/2005 were included. Patients were classified as exposed/ unexposed to treatment according to the presence/absence of at least one prescription for an osteoporosis-related medication in the 6 months following the discharge date. Treatment adherence was calculated for patients who were exposed to bisphosphonate therapy and was defined as at least 80% of treatment coverage during the followup period of 18 months after the discharge date. Hospitalizations, medications, diagnostic tests, laboratory tests and specialist visits during the 18-month follow-up period were collected and classified as osteoporosis-related or non-related to osteoporosis. A total of 12,376 patients were included in the study (mean age ± SD, 79.1 ± 7.5 years), out of which 97.9% (n = 12,110) were hospitalized due to an osteoporosis-related fracture and only 2.1% (n = 266) had general osteoporosis diagnosis. Among the 12,110 women with a fracture, 15.2% (n = 1,845) had a subsequent fracture-related hospitalization (63.8% of the patients had hip fracture). Only 32.3% (n = 4,001) of all included patients was exposed to osteoporosis-related medications and out of those patients exposed to bisphosphonates (n = 860) only 34.2% (n = 294) was adherent to therapy. The average cost per patient was € 4,481, of which € 1,089 was for osteoporosis-related and € 3,392 for non-osteoporosis-related items. The average cost of a matching cohort of patients without hospitalizations for fracture was € 2,339. Among osteoporosis-related costs, 87.0% was due to hospitalizations for subsequent fractures, 1.5% was due to subsquent hospitalizations for osteoporosis, 9.0% was due to medications, 2.5% was due to laboratory or diagnostic/ instrumental tests. Osteoporosis costs after a first hospitalization for fracture were relevant (twice the costs for patients without hospitalizations for fracture), evident in the short run (within the first 24 months following the index fracture) and mostly due to re-hospitalizations for a new typical osteoporotic fracture. This is in mainly relatedto a low exposure to pharmacological therapy and to insufficient treatment adherence. This study and publication were supported by Amgen Dompe and GlaxoSmithKline.

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