“Magnetic resonance imaging [MRI] is not very useful for CPP deposition right now,” she said, but hopes gradient echo or ultrashort echo time MRI may be useful in the future.
Pathogenesis
Shifting to pathogenesis of CPP arthritis, Dr. Rosenthal shared the slow and steady progress being made to better understand the disease’s involved pathways. She reviewed the two phases of CPDD, beginning with crystal formation in cartilage, which remains poorly understood. After crystals are formed, joint damage is mediated. This damage classically occurs when crystals break off from cartilage and produce an inflammatory response through pathways similar to those of gout.
Dr. Rosenthal has focused her research on understanding the crystal formation phase of this disease. The current thinking builds off of the past 60 years of CPP deposition research, which has focused largely on pyrophosphate.
Taking a different approach, Dr. Rosenthal became interested in hereditary forms of CPDD, because she thinks they have a lot to teach us about potential pathogenic pathways relevant to age-related CPP deposition. It’s well known that hereditary CPP deposition clusters at one of two genetic loci, CCAL1 on chromosome 8q and CCAL2 on chromosome 5p.
“We’ve known for about 20 years now the identity of CCAL2. CCAL2 is the protein ANKH [ankylosis protein homolog human gene], which is a multi-pass transmembrane protein that likely transports ATP [adenosine triphosphate] or pyrophosphate from the inside of the cell to the outside of the cell,” she said.
The ANKH mutations associated with CPP deposition are gain-of-function mutations in ANKH, so chondrocytes with too much ANKH overproduce pyrophosphate.
In the lab, when ANKH is silenced in chondrocytes, Dr. Rosenthal and colleagues have seen a significant reduction in ATP that is elaborated by these cells, as well as a significant reduction in pyrophosphate. She says, “So we’ve asked why some metabolic disease associations and hereditary forms of CPP deposition due to CCAL1 can’t easily be explained by alterations of cartilage pyrophosphate.”
A new potential pathway was proposed by a discovery by Dr. Rosenthal and her team showing that osteoprotegerin accounts for the CCAL1 locus in CPDD.6 Osteoprotegerin is a decoy receptor for RANK ligand, a key mediator of bone remodeling. When osteoprotegerin is in excess, it prevents osteoclastogenesis, and when it is scarce, it encourages osteoclastogenesis.
They showed that cartilage is not the primary target of osteoprotegerin or RANK ligand. They hypothesized that a loss of osteoprotegerin function causes increased osteoclasts in subchondral bone.7 Osteoclasts secrete a yet-to-be identified substance that increases pyrophosphate production in the adjacent cartilage. Excess pyrophosphate forms CPP crystals, but also leaks back into subchondral bone and perpetuates a cycle of joint damage.
