Publications

Immunoreceptor tyrosine-based activation motif (ITAM) signaling mediated by DAP12 or Fcepsilon receptor Igamma chain (FcRgamma) have been shown to be critical for osteoclast differentiation and maturation under normal physiological conditions. Their function in pathological conditions is unknown. We studied the role of ITAM signaling during rapid bone remodeling induced by acute estrogen-deficiency in wild-type (WT), DAP12-deficient (DAP12-/-), FcRgamma-deficient (FcRgamma-/-) and double-deficient (DAP12-/-FcRgamma-/-) mice. Six weeks after ovariectomy (OVX), DAP12-/-FcRgamma-/- mice showed resistance to lumbar vertebral body (LVB) trabecular bone loss, while WT, DAP12-/- and FcRgamma-/- mice had significant LVB bone loss. In contrast, all ITAM adapter-deficient mice responded to OVX with bone loss in both femur and tibia of approximately 40%, relative to basal bone volumes. Only WT mice developed significant cortical bone loss after OVX. In vitro studies showed microenvironmental changes induced by OVX are indispensable for enhanced osteoclast formation and function. Cytokine changes, including TGFbeta and TNFalpha, were able to induce osteoclastogenesis independent of RANKL in BMMs from WT but not DAP12-/- and DAP12-/-FcRgamma-/- mice. FSH stimulated RANKL-induced osteoclast differentiation from BMMs in WT, but not DAP12-/- and DAP12-/-FcRgamma-/- mice. Our study demonstrates that although ITAM adapter signaling is critical for normal bone remodeling, estrogen-deficiency induces an ITAM adapter-independent bypass mechanism allowing for enhanced osteoclastogenesis and activation in specific bony microenvironments.

Gabapentin is an anticonvulsant that is widely prescribed for epilepsy and other neuropathic disorders. The pharmacokinetics, particularly the absorption and renal elimination, of gabapentin appear to involve membrane transporters. In this study, we tested the hypothesis that organic cation transporter 1 (OCTN1), a multispecific transporter expressed at the apical membrane in intestine and kidney, plays a role in gabapentin pharmacokinetics and that the common variant of OCTN1, OCTN1-L503F, contributes to variation in the pharmacokinetics of the drug. We observed that OCTN1 facilitates the Na+-independent transport of gabapentin, and that the OCTN1-L503F variant is deficient in gabapentin transport activity in stably transfected HEK-293 cells (fourfold enhanced uptake of gabapentin by OCTN1-503L vs twofold enhanced uptake by OCTN1-L503F, compared to mock-transfected cells). In clinical studies, we found that in subjects homozygous for the L503F variant, gabapentin renal clearance (CL(R)) approximates the glomerular filtration rate (mean+/-SE: 110+/-12 ml/min, n=9), whereas in subjects homozygous for the reference allele, gabapentin undergoes net secretion in the kidney (141+/-7.8 ml/min, n=11, P<0.05). Creatinine clearance and OCTN1 genotype accounted for 56% of the variation in CL(R) and were the only significant predictors of CL(R) (P<0.05). Importantly, OCTN1 genotype was the only significant predictor of net secretion of gabapentin (P<0.008). Oral bioavailability of gabapentin was not affected by OCTN1 genotype. We conclude that OCTN1 contributes to active tubular secretion of gabapentin, and that this effect may be diminished or absent in individuals carrying the OCTN1-L503F polymorphism. These results provide clinical evidence of the role of genetic variation in renal drug transporters in active drug secretion in vivo.

To extend the signal longevity of magnetically excited spins in flowing fluids while in a state of global coherent free precession (GCFP), a refocusing radiofrequency (RF) pulse and bipolar gradient waveforms were combined with the GCFP sequence. The data demonstrate that RF refocusing in the presence of flowing blood is possible, but the improvement in signal amplitude depends on the static magnetic field homogeneity along the direction of motion and the displacement of the spins between the excitation and the RF refocusing pulse, as well as displacement during subsequent RF refocusing pulses. The least amount of phase dispersion and thus the longest lasting signal is obtained with the shortest echo spacing where only one line of data is recorded between two RF refocusing pulses. This approach was successfully used in a phantom and in vivo to image fast and slow blood flow. Depending on the experimental conditions, signal persistence is improved significantly compared to playing the same sequence without RF refocusing, but the improvement is limited by the product of blood flow velocity and the time between RF refocusing pulses.

PURPOSE

Osteonecrosis of the jaw (ONJ) has been observed recently in patients with cancer who are receiving intravenous bisphosphonate (BP) therapy. The incidence of BP-associated ONJ has not been well established. The purpose of this study was to determine the incidence of ONJ in a cohort of patients with multiple myeloma (MM), breast cancer (BC), or prostate cancer (PC) who were receiving BP therapy.

PATIENTS AND METHODS

A retrospective chart review was performed. Medical record numbers were identified by ICD-9 codes: 203.0, 203.01, 174.9, and 185.0 for active MM, MM in remission, BC, and PC, respectively. Patients were included if they were evaluated and/or treated between January 1, 2000, and December 31, 2005, and had received zoledronic acid and/or pamidronate. Patients were excluded if they had a history of radiation therapy to the jaws or of tumors or cysts. ONJ was defined as clinical evidence of "exposed necrotic bone" in the mouth.

RESULTS

Through evaluation of 1,086 patient medical records, it was determined that 447 subjects met the inclusion criteria: 11 of 292 patients with MM (3.8%; 95% confidence interval [CI], 1.6%, 6.0%) had ONJ, as did 2.5% of 81 patients with BC (0%, 6.9%) and 2.9% of 69 patients with PC (0%, 5.9%).

CONCLUSION

The incidence of ONJ associated with intravenous BPs was at least 3.8 per 100 patients with MM, 2.5 per 100 patients with BC, and 2.9 per 100 patients with PC during the 5-year study period. The next phase of this study involves assessment of risk factors that differentiate these patients from those treated with BPs who do not develop ONJ.