Phosphatase inhibition by LB-100 enhances BMN-111 stimulation of bone growth

Area of Science:

• Skeletal biology
• Endocrinology
• Pharmacology

Background:

• Activating FGFR3 mutations and inactivating NPR2 mutations cause achondroplasia (ACH) by reducing chondrocyte cyclic GMP (cGMP).
• Vosoritide (BMN-111), an NPR2 agonist, promotes bone growth in ACH models.
• FGFR3 signaling inactivates NPR2 via dephosphorylation, suggesting phosphatase inhibition could enhance NPR2 agonism.

Purpose of the Study:

• To investigate if a phosphatase inhibitor (LB-100) can enhance vosoritide (BMN-111)-stimulated bone growth in achondroplasia (ACH).
• To evaluate the combined effect of LB-100 and BMN-111 on cGMP production, NPR2 activity, and growth plate parameters in an ACH mouse model.

Main Methods:

• Assessed cGMP production in chondrocytes and NPR2 phosphorylation in primary chondrocytes.
• Utilized ex vivo experiments with Fgfr3Y367C/+ mice (ACH model).
• Measured bone length, cartilage area, chondrocyte differentiation, growth plate proliferation, MAP kinase activity, and skull base anomalies.

Main Results:

• LB-100 counteracted FGF-induced NPR2 dephosphorylation and inactivation, restoring cGMP production.
• The combination of BMN-111 and LB-100 significantly increased bone length, cartilage area, and growth plate proliferation compared to BMN-111 alone.
• Combined treatment normalized chondrocyte differentiation, reduced elevated MAP kinase activity, and improved skull base anomalies in Fgfr3Y367C/+ mice.

Conclusions:

• A phosphatase inhibitor (LB-100) can enhance the efficacy of an NPR2 agonist (BMN-111) in promoting bone growth in achondroplasia.
• This combination therapy strategy shows potential for increasing cGMP levels and treating ACH.
• The findings provide a proof of concept for using dual-acting therapies targeting FGFR3 and NPR2 pathways in skeletal dysplasias.