GPNMB

Transmembrane glycoprotein NMB is a is_associated_with::protein that in humans is encoded by the GPNMB is_associated_with::gene. The mouse and rat orthologues of GPNMB are known as DC-HIL and Osteoactivin (OA), respectively. Two transcript variants encoding 560 and 572 amino acid isoforms have been characterized for this gene in humans. GPNMB is a type I is_associated_with::transmembrane is_associated_with::glycoprotein which shows homology to the pmel17 precursor, a melanocyte-specific protein.

GPNMB has been reported to be expressed in various cell types, including: melanocytes, osteoclasts, osteoblasts, dendritic cells, and it is overexpressed in various cancer types. In melanocytic cells and osteoclasts the GPNMB gene is transcritionally regulated by is_associated_with::Microphthalmia-associated transcription factor. In osteoblast progenitor cells, Osteoactivin works as a positive regulator of osteoblast differentiation during later stages of matrix maturation and mineralization that is mediated at least in part by is_associated_with::BMP-2 in a is_associated_with::SMAD1 dependent manner to promote osteoblast differentiation. In addition, using a rat fracture model, Osteoactivin (OA) enhances the repairing process in bone fracture, demonstrated by its high expression during is_associated_with::chondrogenesis (soft callus) and is_associated_with::osteogenesis (hard callus) compared to the intact femurs that is why Osteoactivin (OA) could be a novel therapeutic agent used to treat generalized is_associated_with::osteoporosis or localized osteopenia during fracture repair by stimulating bone growth and regeneration. Similarly, Osteoactivin expression increases during osteoclast differentiation and it is functionally implicated in this process, possibly by promoting the fusion of osteoclast progenitor cells.

Clinical and functional significance in cancer
GPNMB was originally identified as a gene that was expressed in poorly metastatic human melanoma cell lines and xenografts and not expressed in highly metastatic cell lines. However, several recent studies have identified high GPNMB expression in aggressive is_associated_with::melanoma, is_associated_with::glioma, and is_associated_with::breast cancer specimens. Based on is_associated_with::Immunohistochemical analysis, two studies have shown that GPNMB epression is commonly expressed in breast is_associated_with::tumors. In the first study, GPNMB was detected in 71% (10/14) of breast tumors. In the second study, 64% of human breast tumors express GPNMB in the tumor stroma and an additional 10% of tumors express GPNMB in the tumor is_associated_with::epithelium. In this study it was reported that GPNMB expression in the tumor epithelium was an independent prognostic indicator of breast cancer recurrence. Moreover, epithelial GPNMB expression was most abundant in is_associated_with::triple negative breast cancers and it was found to be a prognostic marker for shorter metastasis-free survival times within this breast cancer subtype. Finally, GPNMB expression in breast cancer cells is capable of promoting is_associated_with::cell migration, invasion, and is_associated_with::metastasis both in vitro and in vivo.

GPNMB as a target for therapy
GPNMB is the target of the antibody glembatumumab (CR011) which is used in the is_associated_with::antibody-drug conjugate is_associated_with::glembatumumab vedotin (CDX-011, CR011-vcis_associated_with::MMAE) which is in clinical trials for is_associated_with::melanoma and is_associated_with::breast cancer. (See is_associated_with::glembatumumab vedotin)