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Animal models of pathologic calcification
1Division of Rheumatology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. imasuda@mcw.edu
Abstract:
Recent progress in genetics and mouse genomics enables researchers to unveil the molecular basis for mouse phenotypes that express pathologic calcification in soft tissue and/or articular tissues. A newly identified multipass transmembrane protein, ANK, appears to function as an inorganic pyrophosphate (PPi) transporter or regulator of PPi transport. Abnormal extracellular PPi (ePPi) metabolism has been implicated in abnormal calcification, decreased concentrations predisposing to basic calcium phosphate (BCP) deposition, and increased concentrations promoting calcium pyrophosphate dihydrate (CPPD) crystal deposition in articular tissues. The chromosomal location of human ANK overlaps the locus identified in several kindreds affected with familial chondrocalcinosis. Deficient generation of ePPi by the ectoenzyme nucleoside triphosphate pyrophosphohydrolase also results in excessive ossification and ectopic deposition of BCP crystals in tiptoe-walking mice and PC-1 null mice. Recent studies reinforce the important regulatory role of ePPi in pathologic and physiologic calcification.
Insights
Genetic insights reveal the ANK protein
Area of Science:
- Genetics
- Molecular Biology
- Biochemistry
Background:
- Pathologic calcification in soft tissues and joints is a complex process.
- Abnormal extracellular pyrophosphate (ePPi) metabolism is linked to various calcification disorders.
- Genetic factors play a crucial role in regulating ePPi levels and calcification.
Purpose of the Study:
- To investigate the molecular basis of pathologic calcification in mice.
- To elucidate the role of the ANK protein in inorganic pyrophosphate (PPi) transport and metabolism.
- To explore the connection between ANK, ePPi levels, and human genetic disorders associated with calcification.
Main Methods:
- Utilizing genetic and mouse genomics approaches.
- Analyzing the function of the ANK transmembrane protein.
- Correlating genetic loci with familial chondrocalcinosis and examining ePPi metabolism in knockout mouse models.
Main Results:
- The ANK protein is identified as a potential inorganic pyrophosphate (PPi) transporter or regulator.
- Altered ePPi metabolism is associated with basic calcium phosphate (BCP) and calcium pyrophosphate dihydrate (CPPD) crystal deposition.
- Deficiencies in ePPi generation lead to ectopic calcification and ossification in specific mouse models.
Conclusions:
- The ANK protein is a key regulator of extracellular pyrophosphate (ePPi) metabolism.
- ePPi plays a critical role in both pathologic and physiologic calcification processes.
- Understanding ANK and ePPi pathways offers insights into treating calcification disorders.