Critical role of AKT protein in myeloma-induced osteoclast formation and osteolysis.

Abnormal osteoclast formation and osteolysis are the hallmarks of multiple myeloma (MM) bone disease, yet the underlying molecular mechanisms are incompletely understood. Here, we show that the AKT pathway was up-regulated in primary bone marrow monocytes (BMM) from patients with MM, which resulted in sustained high expression of the receptor activator of NF-κB (RANK) in osteoclast precursors. The up-regulation of RANK expression and osteoclast formation in the MM BMM cultures was blocked by AKT inhibition. Conditioned media from MM cell cultures activated AKT and increased RANK expression and osteoclast formation in BMM cultures. Inhibiting AKT in cultured MM cells decreased their growth and ability to promote osteoclast formation. Of clinical significance, systemic administration of the AKT inhibitor LY294002 blocked the formation of tumor tissues in the bone marrow cavity and essentially abolished the MM-induced osteoclast formation and osteolysis in SCID mice. The level of activating transcription factor 4 (ATF4) protein was up-regulated in the BMM cultures from multiple myeloma patients. Adenoviral overexpression of ATF4 activated RANK expression in osteoclast precursors. These results demonstrate a new role of AKT in the MM promotion of osteoclast formation and bone osteolysis through, at least in part, the ATF4-dependent up-regulation of RANK expression in osteoclast precursors.

Association of mycobacterial antigen-specific CD4(+) memory T cell subsets with outcome of pulmonary tuberculosis.

OBJECTIVES: Memory T cells are hallmark of acquired immunological responses. The relationship of mycobacterial antigen-specific CD4(+) memory T cell subsets with pulmonary tuberculosis was investigated. METHODS: The mycobacterial antigen-specific CD4(+) T cells were detected based on CD154 expression and phenotypes of memory T cell were analyzed by surface staining of CD45RA and CCR7 and flow cytometrical analysis in patients with pulmonary tuberculosis and in tuberculin-positive healthy controls. The association of antigen-specific CD4(+) memory T cell subsets with disease severity and anti-TB treatment was analyzed in patients with pulmonary tuberculosis. RESULTS: Patients with pulmonary tuberculosis had significantly lower frequencies of antigen-specific central memory T cells (T(CM)) (p=0.019) and higher frequencies of effector memory T cells (T(EM)) (p=0.022) compared with tuberculin-positive healthy controls without tuberculosis. Patients with smear/culture positive results showed lower population frequencies of T(CM) and significantly higher frequencies of T(EM) (p=0.015) than those with smear/culture negative results. Treatment of TB patients with standard antibiotic regimens for more than one month led to significantly increased frequencies of T(CM) (p=0.031). CONCLUSIONS: The frequencies of mycobacterial antigen-specific T(CM) and T(EM) are associated with disease severity of pulmonary tuberculosis and T(CM) are associated with short-term effects of anti-TB chemotherapy.