GREM2 is synthesized as a 168 amino acid monomer and is biologically active as a disulfide-linked homodimer. The protein has six conserved cysteine residues that form a cysteine knot, a structural motif that is crucial for its function. Additionally, GREM2 has two extra cysteine residues located in the loops of the cysteine knot .
The primary function of GREM2 is to inhibit BMP activity. This inhibition is essential for various developmental processes, including osteoblast differentiation and osteogenesis. By antagonizing BMPs, GREM2 helps regulate the balance between bone formation and resorption, which is crucial for maintaining bone health .
Recombinant human GREM2 has been shown to inhibit BMP-4-induced activity in MC3T3-E1 mouse preosteoblast cells. The effective dose (ED50) for this inhibition ranges from 0.03 to 0.12 μg/mL . This inhibitory effect underscores the protein’s role in regulating bone formation and highlights its potential therapeutic applications in bone-related disorders.
Recent genome-wide association studies (GWAS) have identified GREM2 as a novel susceptibility gene for trabecular volumetric bone mineral density (BMD). Variants in the GREM2 gene have been associated with low BMD, particularly in the spine, femoral neck, and total hip. These findings suggest that GREM2 plays a significant role in bone health and may be a potential target for osteoporosis treatment .
Given its role in bone formation and regulation, GREM2 has potential therapeutic applications in treating bone-related disorders such as osteoporosis. By modulating BMP activity, GREM2 could help restore the balance between bone formation and resorption, thereby improving bone density and reducing the risk of fractures .
Recombinant human GREM2 is typically lyophilized from a 0.2 μm filtered solution in HCl and should be reconstituted at 500 μg/mL in 4 mM HCl. The protein is stable for 12 months when stored at -20 to -70°C and for 1 month at 2 to 8°C under sterile conditions after reconstitution. It is important to avoid repeated freeze-thaw cycles to maintain its stability and activity .