Calcification and calcium-containing crystals in osteoarthritis: a molecular exploration of a crystal clear connection

Calcium-containing crystals are a hallmark of osteoarthritis (OA) pathology, necessitating deeper investigation into their role in disease progression and potential therapeutic strategies. This thesis investigates cellular responses to various calcium crystal types and mechanisms driving joint calcification. Basic Calcium Phosphate (BCP) crystals were shown to modulate extracellular matrix protein expression and inducing inflammation via TGF-β signaling, leading to IL-6 secretion. Furthermore, a phosphate-based in vitro model demonstrated TGF-β's role in promoting calcification through increased expression of mineralizing collagens. Using Raman spectroscopy, a novel OA-associated crystal, calcite, was identified, provoking inflammatory and matrix-disrupting responses in joint cells. Additionally, calciprotein particles (CPPs), precursors to BCP crystals, influenced the chondrocyte secretome, with secondary CPPs driving pro-inflammatory and extracellular matrix changes. Finally, a peptide-based anti-calcification therapy targeting the AHSG N-terminal domain was developed, demonstrating reduced OA severity in a rat model. These findings provide critical insights into OA pathology and novel therapeutic avenues.