The gene noggin encodes a member of one of at least four distinct gene families encoding secreted polypeptides that bind to members of the transforming growth factor-beta superfamily, such as BMP, and inhibit the function of these signaling proteins by preventing their interaction with receptors on the cell surface. Other antagonists with related functions include Chordin, Follistatin, Sclerostin and members of the DAN family. These BMP antagonists are assumed to be diffusible and therefore potentially important in the establishment of BMP activity gradients in vivo. Although structurally distinct, members of these gene families have in some cases similar ligand specificity and overlapping patterns of expression, and in the case of Chordin and Noggin these proteins apparently are capable of at least partial compensation for each other. In addition to these multiple secreted BMP antagonists, there are other secreted proteins whose primary function is to overcome this antagonism. Thus, there is a highly complex system to regulate the bioavailability and consequently the activities of BMPs in the extracellular space.
BMP activities are modulated through gene expression, protein processing and by interaction with antagonists. The interplay between BMPs and their antagonists governs developmental and cellular processes as diverse as establishment of the embryonic dorsal-ventral axis, induction of neuronal tissue, and formation of joints in the skeletal system and the neurogenesis in the adult brain. Noggin inhibits BMP signaling by blocking the molecular interfaces of the binding epitopes for both type-I and – II receptors of BMP.
BMPs are important regulators of key events in the processes of bone formation during embryogenesis, postnatal growth, remodeling and regeneration of the skeleton. The BMPs function by binding to a receptor complex that is found on all normal cells and is composed of type-I and –II receptors. The primary unit of bone formation is osteoblast, the bone-forming cell. These osteoblast cells respond to physical loading by transducing signals that alter gene expression patterns. Cbfa (core binding factor), the osteoblast specific transcription factor plays an important role in osteoblast differentiation and function.
Noggin is a homodimer (~32kD) of two monomeric units linked together by a disulfide bond. The monomeric precursor (232aa, human and mouse) is encoded by NOG gene, mapped at human chromosome 17. The mature protein (aa28-232) is secreted as a glycosylated dimer, which binds to BMPs including BMP-2, -4 and–7. The structure of Noggin is very similar to BMP-7. Mutation in Noggin gene leads to skeletal dysplasias characterized by joint fusions.
Source:Recombinant protein corresponding to a DNA sequence encoding the signal peptide from human CD33, joined with aa residues 20-232 from mouse Noggin, fused to the Fc region of human IgG via a polypeptide linker, expressed in a mouse myeloma cell line, NSO.
Molecular Weight:~50kD (calculated). As a result of glycosylation, the recombinant protein migrates as an ~55-60kD protein in SDS-PAGE under reducing conditions.
Biological Activity:Measured by its ability to inhibit rhBMP- 4 induced alkaline phosphatase production by ATDC5 cells. The ED50 for this effect is typically 0.3-1ug/ml in the presence of 75ng/ml of rhBMP-4.
Endotoxin:~1.0ng/1ug of cytokine (LAL method)
Storage and Stability:Lyophilized powder may be stored at -20°C. Stable for 12 months at -20°C. Reconstitute with sterile buffer. Aliquot to avoid repeated freezing and thawing. Store at -20°C. Reconstituted product is stable for 6 months at -20°C. For maximum recovery of product, centrifuge the original vial after thawing and prior to removing the cap. Further dilutions can be made in assay buffer.
