β2-adrenergic signal transduction plays a detrimental role in subchondral bone loss of temporomandibular joint in osteoarthritis

The present study tested whether activation of the sympathetic tone by aberrant joint loading elicits abnormal subchondral bone remodeling in temporomandibular joint (TMJ) osteoarthritis. Abnormal dental occlusion was created in experimental rats, which were then intraperitoneally injected by saline, propranolol or isoproterenol. The norepinephrine contents, distribution of sympathetic nerve fibers, expression of beta-adrenergic receptors (beta-ARs) and remodeling parameters in the condylar subchondral bone were investigated. Mesenchymal stem cells (MSCs) from condylar subchondral bones were harvested for comparison of their beta-ARs, pro-osteoclastic gene expressions and pro-osteoclastic function. Increases in norepinephrine level, sympathetic nerve fiber distribution and beta 2-AR expression were observed in the condylar subchondral bone of experimental rats, together with subchondral bone loss and increased osteoclast activity. beta-antagonist (propranolol) suppressed subchondral bone loss and osteoclast hyperfunction while beta-agonist (isoproterenol) exacerbated those responses. MSCs from experimental condylar subchondral bone expressed higher levels of beta 2-AR and RANKL; norepinephrine stimulation further increased their RANKL expression and pro-osteoclastic function. These effects were blocked by inhibition of beta 2-AR or the PKA pathway. RANKL expression by MSCs decreased after propranolol administration and increased after isoproterenol administration. It is concluded that beta 2-AR signal-mediated subchondral bone loss in TMJ osteoarthritisis associated with increased RANKL secretion by MSCs.