Abstract
BackgroundsAbnormal cartilage calcification is one of the pathological changes of temporomandibular joint (TMJ) osteoarthritis (OA). Recent studies have reported that exosomes can regulate the formation of abnormal calcified nodules in diseases including atherosclerosis and chronic kidney disease. However, the influences of chondrocyte-derived exosomes on abnormal cartilage calcification in TMJ OA are still unclear.MethodsTMJ OA was induced by unilateral anterior crossbite (UAC) for 4, 8, or 12 weeks in rats to observe abnormal calcification in TMJ condylar cartilage and exosome formation. Concomitantly, GW4869, the inhibitor of exosome formation, was locally injected to the TMJ of rats under stimulation of UAC, while the exosomes extracted from primary condylar chondrocytes stimulated with fluid flow shear stress (FFSS) were locally injected to rats TMJ.ResultsAbnormal calcification was enhanced in the degenerative cartilage of TMJ OA in UAC rats, and a large number of exosome-like structures with diameters of 50-150 nm were found in the calcified cartilage together with decreased expression of matrix Gla protein (MGP) and increased expression of CD63, tissue-nonspecific alkaline phosphatase (TNAP) and nucleotide pyrophosphatase/phosphodiesterase-1 (NPP1). After FFSS stimulation, the number of exosomes secreted by chondrocytes and the numbers of calcified nodules were increased in cultured cells, and the protein levels of MGP, TNAP, and NPP1 in exosomes were changed. Inhibition of exosome formation, TNAP, and NPP1 or supplementation with exogenous MGP effectively alleviated FFSS-induced chondrocyte calcification. Local injection of GW4869, the exosome inhibitor, alleviated TMJ OA-related cartilage degeneration and calcification in UAC rats. Local injection of exosomes obtained from chondrocytes stimulated by FFSS to the TMJs of normal rats induced cartilage degeneration and calcification similar to that in TMJ OA.ConclusionsAbnormal biomechanical loading leads to enhanced formation of chondrocyte-derived exosomes, in which promoters of calcification increased and inhibitors decreased, resulting in accelerating abnormal cartilage calcification in TMJ OA. The inhibition of degenerative chondrocyte-derived exosomes is expected to be a new way to prevent and treat TMJ OA.
Highlights
The temporomandibular joint (TMJ) is one of the most common sites of osteoarthritis (OA)
In the TMJ condylar cartilage from rats stimulated with unilateral anterior crossbite (UAC), there were cell-free areas and chondrocyte arrangement was disordered
Our previous study confirmed that basic calcium phosphate (BCP) crystals are the main calcium deposits in the abnormally calcified cartilage of TMJ OA and that BCP crystals can stimulate chondrocytes to produce tumor necrosis factor-α (TNF-α) interleukin-1β (IL-1β) and other proinflammatory factors, aggravating the inflammatory response of OA [5, 29]
Summary
The temporomandibular joint (TMJ) is one of the most common sites of osteoarthritis (OA). TMJ-OA is the most serious subtype of TMJ disorders (TMD), which is a widespread orofacial problem, causing pain and discomfort in patients [1]. In the Chinese mainland, more than 14% of TMD patients present manifestations of TMJ OA on computed tomography examination [2]. Similar to OA in other joints, cartilage calcification is one of the changes in TMJ OA [3, 4]. Calcium crystals, such as basic calcium phosphate (BCP) and calcium pyrophosphate dihydrate (CPPD) crystals, form calcified nodules, which further stimulate inflammation and matrix degradation in cartilage, aggravating the degeneration of cartilage in OA [5,6,7]. The mechanism of abnormal calcification formation in OA cartilage remains to be determined
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