The Calcitonin and Glucocorticoids Combination: Mechanistic Insights into Their Class–Effect Synergy in Experimental Arthritis

Abstract

IntroductionPrevious work reported the anti-arthritic synergy afforded by combining calcitonin (CT) and glucocorticoids (GC). Here we focus on the pairing of elcatonin (eCT) and dexamethasone (Dex), querying whether: i) this was a class-effect action; ii) mechanistic insights could be unveiled; iii) the synergy affected canonical GC adverse effects.MethodsUsing the rat collagen-induced arthritis model, different combinations of eCT and Dex, were administered from disease onset to peak (day 11 to 18). Macroscopic disease score was monitored throughout, with biochemical and histological analyses conducted on plasma and tissues at day 18. The effect on acute hyperglycaemia and liver enzyme message were also assessed.ResultsWhilst eCT alone was inactive, it synergised at 1 µg/kg with low doses of Dex (7.5 or 15 µg/kg) to yield an anti-arthritic efficacy equivalent to a 4- to 7-fold higher Dex dose. Mechanistically, the anti-arthritic synergy corresponded to a marked attenuation in RA-relevant analytes. CXCL5 expression, in both plasma and joint, was markedly inhibited by the co-therapy. Finally, co-administration of eCT did not exacerbate metrics of GC adverse effects, and rescued some of them.ConclusionsWe present evidence of a class-effect action for the anti-arthritic synergy of CT/GC combination, underpinned by the powerful inhibition of joint destruction markers. Furthermore, we identify CXCL5 as a marker for the combination therapy with potential diagnostic and prognostic utility. Substantial GC dose reduction, together with the absence of exacerbated adverse effects, indicated a significant clinical potential for this co-therapy in RA and beyond.

Combining naproxen and a dual amylin and calcitonin receptor agonist improves pain and structural outcomes in the collagen-induced arthritis rat model

“…Combination therapy resulted in maintained bone structure and absence of cartilage lesions, similarly to previous sCT and CT monotherapy OA studies [17, 50]. A previous study combining CT with glucocorticoids, instead of NSAIDs, also demonstrated a chondroprotective effect in the CIA model [21], indicating a beneficial effect of inhibiting bone destruction and inflammation on joint integrity in severe inflammatory arthritic conditions.…”

“…In this study, we demonstrate that combining naproxen with a KBP added significant improvement over naproxen monotherapy. KBP monotherapy did not have significant effects in most structural parameters, similarly to what has previously been reported for CT monotherapy in the CIA model [21, 49]. This may in part be due to the severity of the disease induction being too aggressive for the KBP to overcome, which can be seen within the time to humane endpoint data.…”

“…Interestingly, we observed trends indicating a potential synergistic effect when combining naproxen with KBP in these parameters, but a broader naproxen dose range is needed to validate these effects. A reliable biomarker which might be relevant for the mechanism of action of the combination therapy might be CXCL5 as shown in the CIA study using eCT and dexamethasone [21]. However, an equally important observation could be the elevation of C3M fount in the CIA rats which was subsequently reduced by treatment with the combination therapy.…”

“…In ovariectomized rat models, CT treatment reduced bone turnover, prevented osteopenia [19], and decreased cartilage erosion [20]. An antiarthritic combination therapy of elcatonin (eel calcitonin derivative) and low doses of dexamethasone has been shown to strongly inhibit joint destruction markers in collagen-induced arthritis (CIA) rats [21]. Importantly, sCT had an analgesic effect in clinical studies of patients suffering from Paget’s disease, osteoporotic vertebral fractures, and other musculoskeletal disorders, although the mode of action is unknown [22–25].…”

Calcitonin treatment for osteoarthritis and rheumatoid arthritis – a systematic review and meta-analysis of preclinical data

“…or 5 IU/kg b.w. Untreated DM: injection of streptozotocin and nicotinamide Al-Kashi et al ( 73 ) Rat F NI RA CIA eCT 11 Daily for 1 week i.p. 0.3-10 μg/kg b.w.…”