How can calcium pyrophosphate crystals induce inflammation in hypophosphatasia or chronic inflammatory joint diseases?

Hypophosphatasia (HP) is a rare inborn error of bone and mineral metabolism characterized by a defect in the tissue non-specific alkaline phosphatase (TNSALP) gene. Calcium pyrophosphate dihydrate (CPPD) crystals are known to accumulate as substrates of TNSALP in tissues and joints of patients with HP. In CPPD-induced arthritis these crystals are known to induce an inflammatory response. HP patients do suffer from pain in their lower extremities. However, it is not clear whether CPPD crystals contribute to these musculoskeletal complaints in HP. As long as there is no curative treatment of HP, symptomatic treatment in order to improve clinical features, especially with regard to pain and physical activity, is of major interest to the patients. Knowledge of the mechanisms underlying crystal-induced cell activation, however, is limited. Here we describe recent advances in elucidating the signal transduction pathways activated by CPPD crystals as endogenous “danger signals”. Recent investigations provided evidence that Toll/interleukin-1 receptor (TIR) domain containing receptors including Toll-like receptors (TLRs) and interleukin-1 receptor (IL-1R), as well as the triggering receptor expressed on myeloid cells 1 (TREM-1) and the NACHT-leucin rich repeat and pyrin-domain-containing protein (NALP3) containing inflammasome are essentially involved in acute CPPD crystal-induced inflammation. These receptors are considered in part as components of the innate immune system. Further studies are needed to improve our understanding of the pathophysiological mechanisms leading to inflammation and tissue destruction associated with deposition of microcrystals. They might support the development of new therapeutic strategies for crystal-induced inflammation. Eventually, patients with HP might as well profit from such strategies addressing these metabolic disorders secondary to the gene defect.