No abstract

In chemical carcinogenesis models, GRP94 (gp96) elicits tumor-specific protective immunity. The tumor specificity of this response is thought to reflect immune responses to GRP94-bound peptide antigens, the cohort of which uniquely identifies the GRP94 tissue of origin. In this study, we examined the apparent tissue restriction of GRP94-elicited protective immunity in a 4T1 mammary carcinoma model. We report that the vaccination of BALB/c mice with irradiated fibroblasts expressing a secretory form of GRP94 markedly suppressed 4T1 tumor growth and metastasis. In addition, vaccination with irradiated cells secreting the GRP94 NH2-terminal geldanamycin-binding domain (NTD), a region lacking canonical peptide-binding motifs, yielded a similar suppression of tumor growth and metastatic progression. Conditioned media from cultures of GRP94 or GRP94 NTD-secreting fibroblasts elicited the up-regulation of major histocompatibility complex class II and CD86 in dendritic cell cultures, consistent with a natural adjuvant function for GRP94 and the GRP94 NTD. Based on these findings, we propose that GRP94-elicited tumor suppression can occur independent of the GRP94 tissue of origin and suggest a primary role for GRP4 natural adjuvant function in antitumor immune responses.

Purpose of review To present an updated summary of the relationship between joint shape and the development of osteoarthritis, with a particular focus on osteoarthritis of the hip. Recent findings Osteoarthritis of the hip is highly heritable, with a genetic contribution estimated at 60%. Among the genes that have been linked to this disease are several that are involved in the development and maintenance of joint shape, including members of the Wingless (Wnt) and the bone morphogenetic protein (BMP) family. Several features of hip joint architecture, such as acetabular dysplasia, pistol grip deformity, wide femoral neck, altered femoral neck-shaft angle, appear to play an important role in the pathogenesis of osteoarthritis and may predate the development of osteoarthritis by decades. Summary Gene–environment interactions play a crucial role in the development of osteoarthritis. The architecture of joint shape is determined by a complex sequence spanning embryonic, childhood, and adult life and contributes to the pathogenesis of osteoarthritis.