Male mice with elevated C-type natriuretic peptide-dependent guanylyl cyclase-B activity have increased osteoblasts, bone mass and bone strength

Robinson, Jerid W.; Blixt, Nicholas; Norton, Andrew; Mansky, Kim C.; Ye, Zhou; Aparicio, Conrado; Wagner, Brandon; Benton, Andrew M.; Warren, Gordon L.; Khosla, Sundeep; Gaddy, Dana; Suva, Larry J.; Potter, Lincoln R.

doi:10.1016/j.bone.2020.115320

Cited by 18 publications

(19 citation statements)

References 54 publications

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“…To evaluate the contribution of GC-B dephosphorylation to ACH, we crossed the GC-B 7E/+ mice as originally described as Npr 7E/+ by Shuhaibar et al ( 22 ) or as GC-B 7E/+ by Robinson et al ( 53 ) with the FGFR3 G380R/+ mice originally described as FGFR3 ACH/+ by Lee et al ( 10 ) to generate all the murine lines shown in Figure 1 and Figure 2 . The F1 cross-generated F2 littermates of every possible combination of the FGFR3 and GC-B genes in a mixed C57BL/6 and 129 Sv background.…”

Section: Resultsmentioning

confidence: 99%

Prevention of guanylyl cyclase–B dephosphorylation rescues achondroplastic dwarfism

Wagner¹,

Robinson²,

Lin³

et al. 2021

JCI Insight

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Activating mutations in the fibroblast growth factor receptor 3 (FGFR3) or inactivating mutations in guanylyl cyclase B (GC-B), also known as NPR-B or Npr2, cause short-limbed dwarfism. FGFR3 activation causes dephosphorylation and inactivation of GC-B, but the contribution of GC-B dephosphorylation to achondroplasia (ACH) is unknown. GC-B 7E/7E mice that express a glutamatesubstituted version of GC-B that cannot be inactivated by dephosphorylation were bred with mice expressing FGFR3-G380R, the most common human ACH mutation, to determine if GC-B dephosphorylation is required for ACH. Crossing GC-B 7E/7E mice with FGFR3 G380R/G380R mice increased naso-anal and long (tibia and femur), but not cranial, bone length twice as much as crossing GC-B 7E/7E mice with FGFR3 WT/WT mice from 4 to 16 weeks of age. Consistent with increased GC-B activity rescuing ACH, long bones from the GC-B 7E/7E /FGFR3 G380R/G380R mice were not shorter than those from GC-B WT/WT /FGFR3 WT/WT mice. At two weeks of age, male but not female FGFR3 G380R/G380R mice had shorter long bones and smaller growth plate hypertrophic zones, whereas female but not male GC-B 7E/7E mice had longer bones and larger hypertrophic zones. In two-week old males, crossing FGFR3 G380R/G380R mice with GC-B 7E/7E mice increased long bone length and hypertrophic zone area to levels observed in mice expressing wild type versions of both receptors. We conclude that preventing GC-B dephosphorylation rescues reduced axial and appendicular skeleton growth in a mouse model of achondroplasia.

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Section: Resultsmentioning

confidence: 99%

Prevention of guanylyl cyclase–B dephosphorylation rescues achondroplastic dwarfism

Wagner¹,

Robinson²,

Lin³

et al. 2021

JCI Insight

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“…Recent mouse studies indicate that, in addition to increasing prepubertal bone elongation, phosphorylation of NPR2 increases bone density, due to an increase in the number of active osteoblasts at the bone surface ( 50 ). Because low bone density is one of the key clinical features of ACH ( 51 ), the combination a CNP analog and a phosphatase inhibitor could also have a beneficial impact on bone density for patients with ACH and related conditions.…”

Section: Discussionmentioning

confidence: 99%

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

Shuhaibar¹,

Kaci²,

Egbert³

et al. 2021

JCI Insight

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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 in chondrocytes and severe short stature, causing achondroplasia (ACH) and acromesomelic dysplasia, type Maroteaux, respectively. Previously, we showed that an NPR2 agonist BMN-111 (vosoritide) increases bone growth in mice mimicking ACH ( Fgfr3 Y367C/+ ). Here, because FGFR3 signaling decreases NPR2 activity by dephosphorylating the NPR2 protein, we tested whether a phosphatase inhibitor (LB-100) could enhance BMN-111–stimulated bone growth in ACH. Measurements of cGMP production in chondrocytes of living tibias, and of NPR2 phosphorylation in primary chondrocytes, showed that LB-100 counteracted FGF-induced dephosphorylation and inactivation of NPR2. In ex vivo experiments with Fgfr3 Y367C/+ mice, the combination of BMN-111 and LB-100 increased bone length and cartilage area, restored chondrocyte terminal differentiation, and increased the proliferative growth plate area, more than BMN-111 alone. The combination treatment also reduced the abnormal elevation of MAP kinase activity in the growth plate of Fgfr3 Y367C/+ mice and improved the skull base anomalies. 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.

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“…High circulating Ostn in young mice stimulates bone growth in a manner that depends on NPR-C and endogenous CNP expression (34). Likewise, enhancing CNP signaling through NPR-B regulates bone length, mineralization, and strength in growing mice (35). In mice lacking Sp7 expression in osteocytes, AAV8-Ostn treatment from 3-6 weeks old preserves osteocyte morphology, osteocyte viability, and cortical porosity (20).…”

Section: Discussionmentioning

confidence: 99%

Partial prevention of glucocorticoid-induced osteocyte deterioration with osteocrin gene therapy

Mazur

Andrade

Sato

et al. 2021

Preprint

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Glucocorticoid (GC)-induced osteoporosis and subsequent bone fragility are preceded by death and dysfunction at the cellular level. In particular, short-term glucocorticoid excess suppresses osteocyte remodeling of the surrounding bone mineral, causes apoptosis of osteoblasts and osteocytes, and disrupts homeostatic bone remodeling. Preventing apoptosis and preserving osteocyte morphology and function could be effective means of preventing bone loss during glucocorticoid excess. We hypothesized that osteocrin, which preserves osteocyte viability and morphology in other models where osteocyte defects exist, could prevent osteocyte death and dysfunction in a GC excess model. We used a liver-targeted adeno-associated virus (AAV8) to induce osteocrin overexpression in mice one week prior to implantation with prednisolone or placebo pellets. After 28 days, tissues were collected for micro-CT and histological analysis. GC excess caused the expected reduction in cortical bone thickness and osteocyte canalicular length in control AAV8-treated mice, and these effects were blunted in mice overexpressing osteocrin. However, GC-induced changes in cortical porosity, trabecular bone mass, and gene expression were not prevented by osteocrin. While the mechanism of osteocrin’s effects on osteocyte morphology warrants further investigation, this study does not support a role for this model of osteocrin supplementation to combat the full skeletal effects of GC excess.

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Male mice with elevated C-type natriuretic peptide-dependent guanylyl cyclase-B activity have increased osteoblasts, bone mass and bone strength

Cited by 18 publications

References 54 publications

Prevention of guanylyl cyclase–B dephosphorylation rescues achondroplastic dwarfism

Prevention of guanylyl cyclase–B dephosphorylation rescues achondroplastic dwarfism

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

Partial prevention of glucocorticoid-induced osteocyte deterioration with osteocrin gene therapy

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