The RANKL/RANK/OPG axis is the major determinant of bone remodeling.

• Gene Information: The Opg gene, also known as tumor necrosis factor receptor superfamily, member 11b (osteoprotegerin), encodes a secreted protein, osteoprogegerin,  and is a key gene regulating bone metabolism.
• Protein Expression: OPG is participation in bone homeostasis and expressed in bone marrow, heart, kidney liver and spleen.  Mature OPG is secreted as a homodimer linked by disulfide bonds.
• Signaling Pathway: Functionally, OPG competitively binds to RANKL and blocks the RANKL-RANK signaling cascade. When OPG is deficient, free RANKL accumulates and continuously activates downstream signals, promoting osteoclast differentiation, maturation and hyperactivation. The balance between bone resorption and bone formation is broken, ultimately resulting in decreased bone mass and osteoporosis.
• Therapeutic Applications: The RANKL/RANK/OPG axis acts as a core therapeutic target for high bone-turnover osteoporotic disorders. Current intervention strategies include recombinant OPG protein replacement, RANKL-neutralizing monoclonal antibodies, OPG gene therapy, and small-molecule compounds.

OPG

• The exons 1-5 of mouse Tnfrsf11b gene that encode the full protein were knocked out in B-Opg KO mice.

Mouse-specific OPG expression analysis in homozygous B-Opg KO mice by ELISA. Serum were collected from wild-type mice C57BL/6JNifdc mice (+/+) (female, 16-week-old, n=3) and homozygous B-Opg KO mice (-/-) (female, 16-week-old,n=3), then analyzed by ELISA with mouse-specific OPG ELISA kit (Mouse Osteoprotegerin/TNFRSF11B Immunoassay: R&D, MOP00). Mouse OPG was exclusively detectable in C57BL/6JNifdc mice but not in homozygous B-Opg KO mice. Values are expressed as mean ± SEM.

Micro-CT images of the bones of wild-type C57BL/6JNifdc and homozygous B-Opg KO mice. (A) Representative whole-hindlimb radiographs and magnified radiographs of the distal femur. The distal portion of the femur of the homozygous B-Opg KO mice was highly translucent compared with that of wild-type mice. The distal femur of B-Opg KO mice exhibited marked radiolucency, with severe trabecular bone loss (asterisk) and disrupted growth plate (arrow); wild-type mice showed intact bone architecture without lesions. (B) Quantitative micro-CT analysis of trabecular bone parameters (bone volume/tissue volume (BV/TV) and bone mineral content (BMC)) further confirmed profound bone loss in B-Opg KO mice. Values are expressed as mean ± SEM. Significance was determined by unpaired t test.  *P < 0.05, **P < 0.01, ***P < 0.001.

Q: Is there any difference in bone mineral density (BMD) between wild-type mice and B-Opg KO mice(#114526)?

A: Micro-CT analysis of femurs from homozygous B-Opg KO mice revealed severe trabecular bone and growth plate loss, whereas trabecular BMD exhibited no obvious decline. Trabecular BMD was calculated using the formula TMC/BV. Original data showed that both TMC and BV were significantly reduced in B-Opg KO mice, and the quotient of the two parameters ended up at a similar level to that of wild-type mice, which could be verified from the raw data in the table.