PT - JOURNAL ARTICLE AU - Leia C. Shuhaibar AU - Nabil Kaci AU - Jeremy R. Egbert AU - Léa Loisay AU - Giulia Vigone AU - Tracy F. Uliasz AU - Emilie Dambroise AU - Mark R. Swingle AU - Richard E. Honkanen AU - Laurinda A. Jaffe AU - Laurence Legeai-Mallet TI - The phosphatase inhibitor LB-100 acts synergistically with the NPR2 agonist BMN-111 to improve bone growth AID - 10.1101/2020.09.10.288589 DP - 2020 Jan 01 TA - bioRxiv PG - 2020.09.10.288589 4099 - http://biorxiv.org/content/early/2020/09/11/2020.09.10.288589.short 4100 - http://biorxiv.org/content/early/2020/09/11/2020.09.10.288589.full AB - 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 (Fgfr3Y367C/+), 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 Fgfr3Y367C/+ 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.Competing Interest StatementThe authors have declared no competing interest.