Calcium Pyrophosphate Crystal Formation and Deposition: Where Do we Stand and What Does the Future hold?

Abstract

Purpose of the review: Although calcium pyrophosphate deposition (CPPD) has been known since the 1960s, our understanding of its pathogenesis remains rudimentary. This review aims to illustrate the known mechanisms underlying calcium pyrophosphate (CPP) crystal formation and deposition and explore future directions in research. By examining various perspectives, from basic research to clinical and imaging assessments, as well as new emerging methodologies, we can establish a starting point for a deeper understanding of CPPD pathogenesis.

Recent findings: Recent years have seen significant advances in CPPD research, particularly in the clinical field with the development of the 2023 ACR/EULAR classification criteria for CPPD disease, and in imaging with the introduction of the OMERACT ultrasonographic definitions and scoring system. However, progress in basic research has been slower. New laboratory approaches, such as Raman spectroscopy and omics sciences, offer promising insights that may help piece together the puzzle of CPPD. CPPD is a common yet understudied condition. As the population ages and CPPD becomes more prevalent, there is an urgent need to better understand the disease and the mechanisms involved in crystal formation and deposition, in order to improve diagnosis and therapeutic approaches.

Keywords: Basic science; CPPD; Chondrocalcinosis; Imaging; Pathogenesis.

Fig. 1

Main mechanisms involved in CPP crystal formation. Activated osteoclasts in subchondral bone release TGFβ1 into cartilage, which induces an increase in the levels of nucleotide pyrophosphohydrolase (NTPPH) enzymes and PPi production. Chondrocytes and senescent chondrocytes release articular cartilage vesicles (ACVs) in pericellular regions of extracellular matrix that contain NTPPH enzymes, particularly ENPP1. In the same cells, Ank mediates the extracellular efflux of ATP. In ACVs, ENPP1 hydrolyzes ATP in PPi and AMP. Excess PPi complexes with calcium to form amorphous CPP precursors, which are then converted into more stable CPP crystals and grow within or along collagen fibrils. Once formed in the ECM, CPP crystals may shed into the synovial fluid. TGFβ1: transforming growth factor beta 1; ANK: progressive ankylosis protein; ENPP1: ectonucleotide pyrophosphatase/phosphodiesterase 1; ATP: adenosine triphosphate; AMP: Adenosine monophosphate; PPi: inorganic pyrophosphate; CPP: calcium pyrophosphate

Fig. 2

Ultrasonographic appearance of CPPD in various joint structures. CPP deposits (arrows) appear as hyperechoic (white) deposits (similar to the bone cortex) without creating acoustic shadowing. In fibrocartilage, hyaline cartilage, and synovial. membrane, they present as deposits of variable size and shape, while in tendons, they appear as multiple linear deposits parallel to the tendon’s fibres, not continuous with the bone profile. A) CPP deposits (arrows) in femoral hyaline cartilage, B) in fibrocartilage (knee meniscus traced with a white continuous line), C) in tendons (Achilles tendon), and D) in the synovial membrane (synovial hypertrophy traced with a white continuous line). HC: hyaline cartilage, MM: medial meniscus, AT: Achilles tendon, SM: synovial membrane, SF: synovial fluid

Fig. 3

A hybrid combination of hyperspectral Raman imaging and polarized light microscopy can identify CPP with high specificity. A) Raman spectroscopic imaging can be performed with unprocessed synovial fluid, using standard microscope slides. B) Ordinary polarized light microscopy is used to locate birefringent crystals such as CPP or MSU. Once located, an area of interest is determined by the operator. C) Using the integrated Raman spectroscope, selected crystals are automatically scanned. D) The result: a collection of Raman spectra of the triclinic CPP crystal shown in panel B)