Abstract
This study tested whether activation of adrenoreceptors in chondrocytes has roles in degenerative remodelling of temporomandibular joint (TMJ) and to determine associated mechanisms. Unilateral anterior crossbite (UAC) was established to induce TMJ degeneration in rats. Saline vehicle, α2- and β-adrenoreceptor antagonists or agonists were injected locally into the TMJ area of UAC rats. Cartilage degeneration, subchondral bone microarchitecture and the expression of adrenoreceptors, aggrecans, matrix metalloproteinases (MMPs) and RANKL by chondrocytes were evaluated. Chondrocytes were stimulated by norepinephrine to investigate signal transduction of adrenoreceptors. Increased α2A-adrenoreceptor expression was observed in condylar cartilage of UAC rats, together with cartilage degeneration and subchondral bone loss. Norepinephrine depresses aggrecans expression but stimulates MMP-3, MMP-13 and RANKL production by chondrocytes through ERK1/2 and PKA pathway; these effects were abolished by an α2A-adrenoreceptor antagonist. Furthermore, inhibition of α2A-adrenoreceptor attenuated degenerative remodelling in the condylar cartilage and subchondral bone, as revealed by increased cartilage thickness, proteoglycans and aggrecan expression, and decreased MMP-3, MMP-13 and RANKL expressions in cartilage, increased BMD, BV/TV, and decreased Tb.Sp in subchondral bone. Conversely, activation of α2A-adrenoreceptor intensified aforementioned degenerative changes in UAC rats. It is concluded that activation of α2A-adrenergic signal in chondrocytes promotes TMJ degenerative remodelling by chondrocyte-mediated pro-catabolic activities.
Highlights
The paracrine effects of norepinephrine are mediated via the adrenoreceptor family comprising α1, α2 and β subtypes; each subtype is further classified into three isoforms[3]
3, matrix metalloproteinase-13 (MMP-13) and RANKL by chondrocytes after NE stimulation combined with yohimbine (Yoh), U0126 or LY294002 (LY) treatment (N = 3). *P < 0.05, **P < 0.01: vs vehicle-treated chondrocytes; #P < 0.05, ##P < 0.01: vs the corresponding NE-treated chondrocytes
PCR of the expression of aggrecan, MMP-3, MMP-13 and RANKL by chondrocytes after norepinephrine stimulation combined with different inhibitors of adrenoreceptors (N = 5)
Summary
The paracrine effects of norepinephrine are mediated via the adrenoreceptor family comprising α1, α2 and β subtypes; each subtype is further classified into three isoforms[3]. Increased RANKL/OPG ratio in chondrocytes derived from the knee joint cartilage of osteoarthritis patients[18] or experimental animals[19], resulted in increased osteoclast activity and subchondral bone loss. This RANKL-induced osteoclastogenesis was further enhanced by MMP-1317. To date, it is unknown whether expressions of cartilage ECM components and degrading factors of the osteochondral complex by chondrocytes would be affected by the sympathetic tone during osteoarthritis progression. This UAC rat model was used to determine the longitudinal expression profile of chondrocytic adrenoreceptors, and the effects and underlying mechanism of norepinephrine on the anabolic and catabolic activities of chondrocytes were examined. Whether injection of adrenoreceptor antagonists or agonists into the local TMJ region could reverse/aggravate TMJ degenerative remodelling were investigated
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