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    • One important discovery of our

    2021-12-31

    One important discovery of our study is the identification of a pharmacological mechanism for the macrolide antibiotic erythromycin (EM) in promoting joint health. EM is a commonly used antibiotic that directly binds bacterial ribosomes to inhibit protein synthesis [66]. Although EM-like macrolide Dyphylline australia have anti-inflammatory activities in the lung and bone in an antibiotic-independent manner, its chondroprotective effect in the joint has only been described in our recent study [17], [18], [19], [20], [21], [22]. However, in all these systems, how EM exerts its effect on eukaryotic cells had not been elucidated. EM was previously shown to be capable of binding to the motilin receptor [67], [68]. The natural ligand of the motilin receptor is motilin, a peptide that stimulates GI motility [69]. Interestingly, in the mouse, motilin and its receptors are pseudogenes [70], [71]. Since our in vivo experiments indicate a joint protective effect of EM, we reasoned that the motilin receptor could not be mediating the activity of EM in the mouse [22]. The ghrelin receptor and the motilin receptor share 50% identity, and both ligands have very similar roles in promoting gastric emptying and GI motility [69], [72], [73]. While an EM derivative binds to the ghrelin receptor, it is still not known whether EM itself can directly bind to the receptor. Nevertheless, our subsequent experiments indicated that ghrelin can compete with EM in ghrelin receptor association, and that the effect of EM is lost when the ghrelin receptor is not present. Thus, our data strongly suggest that EM functionally acts through the ghrelin receptor to exert its activity in the mouse. However, this does not exclude the motilin receptor as a mediator of the activity of EM in species where motilin signaling is present, as in humans [70]. While the binding affinity of EM to the ghrelin receptor in vivo and in vitro is now known, our data indicate that the association of EM with chondrocytes can be outcompeted by a much lower concentration of ghrelin, suggesting that it is not likely that EM will inhibit the activity of endogenous ghrelin (Fig. 3F). Furthermore, in the case of OA, when ghrelin concentration is already lower in the synovial fluid [61], additional EM might stimulate the ghrelin receptor to exert its beneficial effect. However, in order to select the most appropriate macrolide for OA therapy, other EM-like antibiotics, such as azithromycin or clarithromycin, would also need to be investigated for similar effects on the joint as EM. Systemic administration of macrolide antibiotics may raise the concern of antibiotic resistance. However, this concern may be allayed by intra-articular injection of antibiotics or by administration of non-antibiotic macrolides such as EM900. One limitation of this study is that we have not demonstrated whether EM900 acts through the ghrelin receptor to exert its activity, even though we have shown this is the case for EM. Another limitation is that only one mouse model for joint inflammation and destruction was tested. Since there are many causes of OA, it will be important to evaluate the role of these reagents in other models, such as the Destabilization of the Medial Meniscus (DMM), meniscectomy, or obesity-induced OA model [74], [75], [76], [77], [78]. Future studies will also involve the delivering of EM into OA joints after OA has initiated for a period of time so that its therapeutic potential can be evaluated. The only study on EM in human OA was restricted to a single clinical trial combining EM with acetaminophen [79]. While joint effusion and pain was reduced [79], changes in joint structure were not assessed and erythromycin efficacy as a monotherapy was also not determined [79]. Our study has characterized the structural changes of the joint and uncovered a new mechanism for EM to act as an anti-inflammatory reagent. While ghrelin has been reported to alleviate pain in the carrageenan intraplantar injection model [80], it remains unclear whether such parallels exist in the knee joint. Thus, future experiments would be designed to determine whether EM and ghrelin can provide pain relief in arthritic joints, to thoroughly explore the potential of these molecules as OA therapeutics.