Deficiency of sorting nexin 10 prevents bone erosion in collagen-induced mouse arthritis through promoting NFATc1 degradation.

OBJECTIVE: Periarticular and subchondral bone erosion in rheumatoid arthritis caused by osteoclast differentiation and activation is a critical index for diagnosis, therapy and monitoring of the disease. Sorting nexin (SNX) 10, a member of the SNX family which functions in regulation of endosomal sorting, has been implicated to play an important clinical role in malignant osteopetrosis. Here we studied the roles and precise mechanisms of SNX10 in the bone destruction of collagen-induced arthritis (CIA) mice. METHODS: The role of SNX10 in bone destruction was evaluated by a CIA mice model which was induced in male SNX10(-/-) mice and wild type littermates. The mechanism was explored in osteoclasts induced by receptor activator of nuclear factor κB ligand from bone marrow mononuclear cells of wild type and SNX10(-/-) mice. RESULTS: SNX10 knockout prevented bone loss and joint destruction in CIA mice with reduced serum levels of TNF-α, interleukin 1ß and anticollagen IgG 2α antibody. SNX10 deficiency did not block osteoclastogenesis, but significantly impaired osteoclast maturation and bone-resorption function by disturbing the formation of actin belt. The production of TRAP, CtsK and MMP9 in SNX10(-/-) osteoclasts was significantly inhibited, and partially restored by SNX10 overexpression. We further demonstrated that the degradation of NFATc1 was accelerated in SNX10(-/-) osteoclasts causing an inhibition of integrin ß3-Src-PYK2 signalling. CONCLUSIONS: Our study discloses a crucial role and novel mechanism for SNX10 in osteoclast function, and provides evidence for SNX10 as a promising novel therapeutic target for suppression of immune inflammation and bone erosion in rheumatoid arthritis.

Expression of MAGE-A11 in breast cancer tissues and its effects on the proliferation of breast cancer cells.

The melanoma-associated antigen (MAGE) genes are commonly expressed in tumors, but the function of many of these genes remains unknown. Here, we investigated the expression of one family member, MAGE-A11, in breast cancer tissues and corresponding adjacent normal tissues. MAGE-A11 expression was assessed in breast cancer tissues and adjacent normal tissues from 100 women by immunohistochemistry. MAGE-A11 was significantly more highly expressed in breast tumors (56% of samples) compared to normal tissues (0%; P<0.05). Additionally, its expression in breast tumors was investigated in relation to various clinicopathological features, including patient age, tumor stage and volume, and lymph node metastasis. MAGE-A11 protein expression was correlated with expression of the human epidermal growth factor receptor-2 (HER-2) and estrogen receptor (ER)-ß (P<0.05), but not with age, pathological type, histological grade, clinical stage, tumor size or lymph node metastasis, or ER-α, progesterone receptor (PR) or amplified in breast cancer 1 (AIB-1) expression. To determine how its expression affects cancer cell proliferation in vitro, MCF-7 human breast cancer cells were transfected with pCMV-AC-MAGE-A11-GFP. MTT colorimetry and colony-forming assays indicated that MAGE-A11 overexpression significantly increased breast cancer cell proliferation and the ability to form colonies (P<0.05). These findings indicate that MAGE-A11, similarly to HER-2 and ER-ß, may be an important diagnostic or prognostic indicator in breast cancer and potentially promotes tumor proliferation.