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The Role of the Progressive Ankylosis Gene in Physiological & Pathological Mineralization
Physiological mineralization is important for bone development and for the proper function of bones. Mineralization must be restricted to certain sites, however, as uncontrolled or pathological mineralization can have severe adverse consequences. For example, mineralization of articular cartilage leads to its destruction, while mineralization of cardiovascular tissues leads to morbidity or even death. In the Kirsch Lab, we investigate the role of the progressive ankylosis gene (ank) in physiological and pathological mineralization.
![Graphic of Proposed Model Showing how Ank Regulates Physiological and Pathological Mineralization](/research/kirsch-lab/sites/default/files/kirsch-lab-ank-model.gif)
Normal articular chondrocytes express low amounts of Ank, which in turn transports intracellular pyrophosphate (PPi) to the extracellular milieu. Extracellular pyrophosphate acts as an inhibitor of mineralization. In osteoarthritic cartilage, Ank protein expression is highly upregulated. Upregulated Ank expression results in an increased extracellular pyrophosphate concentration. In the absence of alkaline phosphatase, increased extracellular pyrophosphate results in calcium pyrophosphate crystal (CPPD) deposition in articular cartilage. If articular chondrocytes or growth plate chondrocytes express alkaline phosphatase, then extracellular pyrophosphate is hydrolyzed to inorganic phosphate (Pi), resulting in basic calcium phosphate (BCP) crystal deposition. Furthermore, inorganic phosphate is transported back into the cell, where it acts as a signaling molecule stimulating terminal differentiation and mineralization events.
To understand the mechanisms regulating biomineralization, our laboratory is conducting experiments to determine the role of Ank, a protein that transports intracellular pyrophosphate to the extracellular milieu in normal and pathological mineralization of cartilage and other tissues. Pyrophosphate is hydrolyzed to inorganic phosphate by alkaline phosphatase, an enzyme present in hypertrophic chondrocytes and bone cells. Mutations in the human ank gene result in hypermineralization and diseases such as craniometaphyseal dysplasia and chondrocalcinosis.
Our goal is to determine how Ank regulates extracellular pyrophosphate concentration and subsequent mineralization. So far, we have determined that expression of ank in articular chondrocytes that do not express alkaline phosphatase results in calcium pyrophosphate crystals, whereas expression of ank in articular chondrocytes that express alkaline phosphatase results in basic calcium phosphate crystal deposition.
Interestingly, both forms of crystals are found in patients with osteoarthritis, and these crystals are main contributors to cartilage destruction during osteoarthritis. More importantly, our research provides evidence that inorganic phosphate not only is a component of basic calcium phosphate crystals but is transported back into the cell where it acts as a signaling molecule stimulating terminal differentiation and mineralization events of chondrocytes during development and pathology.