Publications

Induction of effective osteoclastogenesis by RANK (receptor activator of NF-kappaB) requires costimulation by ITAM-coupled receptors. In humans, the TREM-2 (triggering receptor expressed on myeloid cells 2) ITAM-coupled receptor plays a key role in bone remodeling, as patients with TREM-2 mutations exhibit defective osteoclastogenesis and bone lesions. We have identified a new rapidly induced costimulatory pathway for RANK signaling that is dependent on TREM-2 and mediated by calcium signaling. TREM-2-dependent calcium signals are required for RANK-mediated activation of calcium/calmodulin-dependent protein kinase (CaMK)II and downstream MEK and ERK MAPKs that are important for osteoclastogenesis. IL-10 inhibited RANK-induced osteoclastogenesis and selectively inhibited calcium signaling downstream of RANK by inhibiting transcription of TREM-2. Down-regulation of TREM-2 expression resulted in diminished RANKL-induced activation of the CaMK-MEK-ERK pathway and decreased expression of the master regulator of osteoclastogenesis NFATc1. These findings provide a new mechanism of inhibition of human osteoclast differentiation. The results also yield insights into crosstalk between ITAM-coupled receptors and heterologous receptors such as RANK, and they identify a mechanism by which IL-10 can suppress cellular responses to TNFR family members.

By using random PCR amplification, shotgun sequencing and sequence similarity searches, we analysed nucleic acids present in cell cultures inoculated with samples from unexplained cases of encephalitis. We identified a divergent human papillomavirus (HPV) sequence originating from a rectal swab. The full genome was amplified by inverse PCR and sequenced. The prototype of the sixth gammapapillomavirus species, HPV116, was not found in the patient's cerebrospinal fluid or respiratory secretions, nor in culture supernatants from other unexplained cases of encephalitis, indicating that its identification in an encephalitis patient was accidental.