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Effect of Roflumilast, a Selective PDE4 Inhibitor, on Bone Phenotypes in ADO2 Mice
Imranul Alam1, Sara L Hardman2, Rita L Gerard-O'Riley2
1Division of Endocrinology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. ialam@iu.edu.
Abstract:
Autosomal Dominant Osteopetrosis type II (ADO2) is a rare bone disease of impaired osteoclastic bone resorption that usually results from heterozygous missense mutations in the chloride channel 7 (CLCN7) gene. We previously created mouse models of ADO2 (p.G213R) with one of the most common mutations (G215R) as found in humans and demonstrated that this mutation in mice phenocopies the human disease of ADO2. Previous studies have shown that roflumilast (RF), a selective phosphodiesterase 4 (PDE4) inhibitor that regulates the cAMP pathway, can increase osteoclast activity. We also observed that RF increased bone resorption in both wild-type and ADO2 heterozygous osteoclasts in vitro, suggesting it might rescue bone phenotypes in ADO2 mice. To test this hypothesis, we administered RF-treated diets (0, 20 and 100 mg/kg) to 8-week-old ADO2 mice for 6 months. We evaluated bone mineral density and bone micro-architecture using longitudinal in-vivo DXA and micro-CT at baseline, and 6-, 12-, 18-, and 24-week post-baseline time points. Additionally, we analyzed serum bone biomarkers (CTX, TRAP, and P1NP) at baseline, 12-, and 24-week post-baseline. Our findings revealed that RF treatment did not improve aBMD (whole body, femur, and spine) and trabecular BV/TV (distal femur) in ADO2 mice compared to the control group treated with a normal diet. Furthermore, we did not observe any significant changes in serum levels of bone biomarkers due to RF treatment in these mice. Overall, our results indicate that RF does not rescue the osteopetrotic bone phenotypes in ADO2 heterozygous mice.
Insights
Roflumilast (RF) did not improve bone density or micro-architecture in mouse models of Autosomal Dominant Osteopetrosis type II (ADO2). This phosphodiesterase 4 inhibitor did not rescue impaired osteoclastic bone resorption in ADO2 mice.
Area of Science:
- Bone Biology and Disease
- Genetics and Rare Diseases
- Pharmacology and Therapeutics
Background:
- Autosomal Dominant Osteopetrosis type II (ADO2) is a rare genetic bone disorder characterized by impaired osteoclast function, often caused by CLCN7 gene mutations.
- Mouse models carrying common human ADO2 mutations phenocopy the human disease, providing a platform for therapeutic investigation.
- Roflumilast (RF), a phosphodiesterase 4 (PDE4) inhibitor, is known to modulate the cAMP pathway and has shown potential to increase osteoclast activity.
Purpose of the Study:
- To investigate the therapeutic potential of roflumilast (RF) in rescuing bone phenotypes in a mouse model of Autosomal Dominant Osteopetrosis type II (ADO2).
- To evaluate the effects of RF on bone mineral density, bone micro-architecture, and serum bone biomarkers in ADO2 mice.
Main Methods:
- Mice with a common ADO2 mutation (p.G213R) were fed diets containing 0, 20, or 100 mg/kg of RF for six months.
- Bone mineral density (aBMD) and bone micro-architecture were assessed longitudinally using in vivo DXA and micro-CT.
- Serum levels of bone turnover biomarkers, including CTX, TRAP, and P1NP, were measured at specified time points.
Main Results:
- RF treatment did not significantly improve whole body, femur, or spine aBMD in ADO2 mice compared to controls.
- No significant improvements in trabecular bone volume fraction (BV/TV) in the distal femur were observed with RF administration.
- Serum bone biomarker levels remained unchanged, indicating no significant effect of RF on bone resorption or formation markers in this model.
Conclusions:
- Roflumilast (RF) does not appear to rescue the osteopetrotic bone phenotypes in heterozygous ADO2 mice.
- The in vitro observation of increased osteoclast activity by RF was not translated into a therapeutic benefit in vivo for ADO2.
- Further research may be needed to explore alternative therapeutic strategies for Autosomal Dominant Osteopetrosis type II.
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