Stage-specific and location-specific cartilage calcification in osteoarthritis development

Abstract

ObjectivesThis study investigated the stage-specific and location-specific deposition and characteristics of minerals in human osteoarthritis (OA) cartilages via multiple nano-analytical technologies.MethodsNormal and OA cartilages were serially sectioned for micro-CT, scanning electron microscopy with energy dispersive X-ray spectroscopy, micro-Raman spectroscopy, focused ion beam scanning electron microscopy, high-resolution electron energy loss spectrometry with transmission electron microscopy, nanoindentation and atomic force microscopy to analyse the structural, compositional and mechanical properties of cartilage in OA progression.ResultsWe found that OA progressed by both top-down calcification at the joint surface and bottom-up calcification at the osteochondral interface. The top-down calcification process started with spherical mineral particle formation in the joint surface during early-stage OA (OA-E), followed by fibre formation and densely packed material transformation deep into the cartilage during advanced-stage OA (OA-A). The bottom-up calcification in OA-E started when an excessive layer of calcified tissue formed above the original calcified cartilage, exhibiting a calcified sandwich structure. Over time, the original and upper layers of calcified cartilage fused, which thickened the calcified cartilage region and disrupted the cartilage structure. During OA-E, the calcified cartilage was hypermineralised, containing stiffer carbonated hydroxyapatite (HAp). During OA-A, it was hypomineralised and contained softer HAp. This discrepancy may be attributed to matrix vesicle nucleation during OA-E and carbonate cores during OA-A.ConclusionsThis work refines our current understanding of the mechanism underlying OA progression and provides the foothold for potential therapeutic targeting strategies once the location-specific cartilage calcification features in OA are established.

Micro Trojan horses: Engineering extracellular vesicles crossing biological barriers for drug delivery

“…In addition to accelerating cartilage destruction by promoting joint inflammation, EV can also regulate the calcification process of articular cartilage. Pathological calcification of cartilage occurs in the early stage of OA, which can lead to the degeneration of joint tissue and play an important role in promoting the progress of OA 144–146 . Matrix vesicles (MVs) are a subset of EVs rich in calcium and phosphate and containing organic substances such as acidic proteins.…”

“…Pathological calcification of cartilage occurs in the early stage of OA, which can lead to the degeneration of joint tissue and play an important role in promoting the progress of OA. [144][145][146] Matrix vesicles (MVs) are a subset of EVs rich in calcium and phosphate and containing organic substances such as acidic proteins. MVs can regulate the steady state of calcium and phosphate ions in the extracellular matrix and the ratio of inorganic phosphate to inorganic pyrophosphate and provide the nucleation site of calcium phosphate crystals, which plays an important role in the early pathological calcification of cartilage in OA.…”

Lysosomal destabilization: A missing link between pathological calcification and osteoarthritis

“…Cartilage calcification by hydroxyapatite has been recognized as a hallmark of osteoarthritis and presumably initiate osteoarthritis. It strongly correlates with the severity of osteoarthritis, but no strategies are available to prevent crystal deposition and permit mineral dissolution in osteoarthritic cartilage so far [ [10] , [11] , [12] ]. The hydroxyapatite crystallites within osteoarthritic cartilage have been associated with inflammation in osteoarthritis [ [11] , [12] , [13] , [14] ].…”

“…It strongly correlates with the severity of osteoarthritis, but no strategies are available to prevent crystal deposition and permit mineral dissolution in osteoarthritic cartilage so far [ [10] , [11] , [12] ]. The hydroxyapatite crystallites within osteoarthritic cartilage have been associated with inflammation in osteoarthritis [ [11] , [12] , [13] , [14] ]. However, the exact mechanism in which hydroxyapatite initiates inflammation is contentious [ 11 ].…”

“…The hydroxyapatite crystallites within osteoarthritic cartilage have been associated with inflammation in osteoarthritis [ [11] , [12] , [13] , [14] ]. However, the exact mechanism in which hydroxyapatite initiates inflammation is contentious [ 11 ].…”