The phosphatase inhibitor LB-100 acts synergistically with the NPR2 agonist BMN-111 to improve bone growth

Combining the phosphatase inhibitor LB-100 with the NPR2 agonist BMN-111 resulted in a ∼25% increase in femur growth in a mouse model of achondroplasia, suggesting a potential avenue for enhancing bone growth.

Summary and findings

This study evaluated the effects of the phosphatase inhibitor LB-100 in combination with the NPR2 agonist BMN-111 (vosoritide) on bone growth in a mouse model of achondroplasia. The combination treatment resulted in a ∼25% increase in femur growth compared to BMN-111 alone. The study aimed to explore potential therapeutic strategies for enhancing bone growth in conditions associated with impaired NPR2 signaling.

Abstract

<h4>ABSTRACT</h4> Activating mutations in fibroblast growth factor receptor 3 (FGFR3) and inactivating mutations in the natriuretic peptide receptor 2 (NPR2) guanylyl cyclase both result in decreased production of cyclic GMP (cGMP) in chondrocytes and severe short stature, causing achondroplasia (ACH) and acrosomelic dysplasia type Maroteaux, respectively. Previously we showed that an NPR2 agonist BMN-111 (vosoritide) increases bone growth in mice mimicking ACH ( Fgfr3 Y367C/+ ), and that in control growth plate chondrocytes, FGFR3 signaling decreases NPR2 activity by dephosphorylating the NPR2 protein. Here we tested whether a phosphatase inhibitor (LB-100) could enhance bone growth in ACH. In ex vivo imaging experiments using a FRET sensor to measure cGMP production in chondrocytes of living tibias from newborn mice, LB-100 counteracts the FGF-induced dephosphorylation and inactivation of NPR2. In ex vivo experiments with Fgfr3 Y367C/+ mice, LB-100 in combination with BMN-111 increases the rate of femur growth by ∼25% vs BMN-111 alone, restores chondrocyte terminal differentiation, increases the proliferative growth plate area of the femur, and reduces the activity of the MAP kinase pathway. Our results provide a proof of concept that a phosphatase inhibitor could be used together with an NPR2 agonist to enhance cGMP production as a therapy for ACH. <h4>GRAPHICAL ABSTRACT</h4>

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