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.

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.

The alveolar surface comprises >99% of the internal surface area of the lungs. At birth, the fetal lung rapidly converts from a state of net fluid secretion, which is necessary for normal fetal lung development, to a state in which there is a minimal amount of alveolar liquid. The alveolar surface epithelium facing the air compartment is composed of TI and TII cells. The morphometric characteristics of both cell types are fairly constant over a range of mammalian species varying in body weight by a factor of approximately 50,000. From the conservation of size and shape across species, one may infer that both TI and TII cells also have important conserved functions. The regulation of alveolar ion and liquid transport has been extensively investigated using a variety of experimental models, including whole animal, isolated lung, isolated cell, and cultured cell model systems, each with their inherent strengths and weaknesses. The results obtained with different model systems and a variety of different species point to both interesting parallels and some surprising differences. Sometimes it has been difficult to reconcile results obtained with different model systems. In this section, the primary focus will be on aspects of alveolar ion and liquid transport under normal physiologic conditions, emphasizing newer data and describing evolving paradigms of lung ion and fluid transport. We will highlight some of the unanswered questions, outline the similarities and differences in results obtained with different model systems, and describe some of the complex and interweaving regulatory networks.