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High-dose oral pyrophosphate inhibits connective tissue calcification in Abcc6 null mice but may affect bone
Ibtesam Rajpar1, Nicholas Yancy1, Jacob Beiriger1
1Department of Orthopaedic Surgery, Thomas Jefferson University, 1025 Walnut Street, Philadelphia, PA 19107, United States.
Abstract:
Pseudoxanthoma elasticum (PXE) is a rare inherited disorder marked by abnormal calcium phosphate deposition in soft connective tissues, particularly the skin, arteries, and eyes. It is caused by inactivating mutations in the ABCC6 gene, which encodes a hepatic efflux transporter. Loss of ABCC6 function leads to reduced plasma levels of pyrophosphate (PPi), a key inhibitor of calcification, thereby promoting ectopic mineralization. Oral PPi therapy has emerged as a potential treatment, but its effectiveness is uncertain. Most ingested PPi is hydrolyzed in the gut to inorganic phosphate, which may worsen calcification. Moreover, its impact on mineralized tissues remains largely unexplored. Abcc6-/- mice closely mimic human PXE and are widely used in preclinical studies. Although patients are most concerned about ocular complications, eye calcification is rarely assessed in translational studies using Abcc6-/- mice. Using micro-CT, we found that ectopic calcification at the ciliary margin is a reliable marker of ocular disease progression in these mice. Administering PPi in drinking water at concentrations up to 90 mM did not increase calcification in skin or eyes. However, only very high doses effectively prevented ectopic calcification-doses that would equate to an impractical 2.5 g/kg/d of disodium PPi in humans. These high doses also led to PPi accumulation in bone and negatively affected bone structure and strength. In summary, only supraphysiological doses of orally administered PPi inhibited ectopic calcification in Abcc6-/- mice, but these doses are not feasible for human use and may compromise bone function. These data are especially important considering the currently ongoing clinical trial evaluating the safety and efficacy of oral PPi administration as a treatment for PXE.
Insights
Oral pyrophosphate (PPi) therapy for Pseudoxanthoma elasticum (PXE) is ineffective at practical doses. High doses of PPi showed limited benefit in mice and negatively impacted bone health, raising concerns for human trials.
Area of Science:
- Biochemistry
- Genetics
- Medical Research
Background:
- Pseudoxanthoma elasticum (PXE) is a rare genetic disorder characterized by ectopic calcification due to ABCC6 mutations.
- Reduced pyrophosphate (PPi) levels are implicated in PXE pathogenesis, making oral PPi a potential therapeutic strategy.
- The efficacy and safety of oral PPi therapy, particularly its impact on ocular and bone health, remain largely uninvestigated.
Purpose of the Study:
- To evaluate the effectiveness of oral pyrophosphate (PPi) administration in preventing ectopic calcification in a mouse model of Pseudoxanthoma elasticum (PXE).
- To assess the impact of oral PPi on ocular and dermal calcification, and to explore its effects on bone structure and strength.
- To determine the feasibility of oral PPi therapy for human PXE treatment based on preclinical findings.
Main Methods:
- Utilized Abcc6-/- mice as a model for Pseudoxanthoma elasticum (PXE).
- Administered varying concentrations of disodium PPi in drinking water.
- Assessed ectopic calcification in skin and eyes using micro-computed tomography (micro-CT).
- Analyzed bone structure and strength following PPi treatment.
Main Results:
- Oral PPi administration, even at high concentrations (up to 90 mM), did not significantly increase calcification in the skin or eyes of Abcc6-/- mice.
- Only supraphysiological doses of oral PPi demonstrated inhibition of ectopic calcification.
- These high doses led to PPi accumulation in bone, negatively affecting bone structure and strength, rendering them impractical for human use.
Conclusions:
- Oral PPi therapy is unlikely to be effective for Pseudoxanthoma elasticum (PXE) at doses feasible for human administration.
- High-dose PPi treatment in mice showed limited efficacy in preventing ectopic calcification and posed risks to bone health.
- These findings raise significant concerns regarding the ongoing clinical trial evaluating oral PPi for PXE treatment.
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