Treatment of naïve rats with L-006235 (100 mg/kg) significantly reduced the serum CTX-I levels at 1 hour after dose by 20%, compared with baseline (Fig. 7A). In vehicle-treated naïve rats, serum CTX-I levels were instead increased by 6% at 1 hour, compared with baseline. The reduction in CTX-I levels by L-006235 was statistically significant vs baseline (P < 0.05) and vs vehicle (P < 0.05). No significant reductions in CTX-I were observed at 3 hours after L-006235 administration. Serum CTX-I levels are known to vary on food intake, and thus the results at 6 and 24 hours after dose (when the animals were allowed food again) were not conclusive. Similarly, serum CTX-II levels were reduced in L-006235–treated rats at 1 hour (by 42%) and 3 hours after dose (by 24%), compared with baseline (Fig. 7B). The reductions were statistically significant vs baseline (P < 0.05) at 1 hour and statistically significant vs vehicle at 1 hour (P < 0.001) and 3 hours (P < 0.05). The CTX-II levels returned to baseline at 6 hours after dose. In vehicle-treated rats, serum CTX-II levels were increased by 26% and 19%, compared with baseline, at 1 hour and 3 hours, respectively. Overall, the results indicate a significant, but transient in vivo target engagement of cathepsin K by L-006235.
This study reports for the first time the beneficial effects of a cathepsin K inhibitor on the development of pain behaviour in a well-established rodent model of OA pain. Oral treatment with the cathepsin K inhibitor L-006235 significantly attenuated the development of pain behaviour in the MIA model of OA pain. Inhibitory effects of L-006235 were most evident on weight-bearing asymmetry, which was significantly attenuated from day 14 and then maintained for the duration of the study. Only the higher dose of preventative L-006235 significantly blocked the lowering of hind PWTs at the final 2 time points of the study. Therapeutic treatment with L-006235 from 14 days after induction of the MIA model significantly prevented further changes in weight-bearing asymmetry; however, L-006235 did not significantly reverse the already established weight-bearing asymmetry. In addition, therapeutic treatment with L-006235 did not alter lowered hind PWTs in MIA rats, compared with vehicle. Pharmacokinetic analysis confirmed that the exposure to L-006235 was higher at the 100-mg/kg dose, compared with the 30-mg/kg dose.
The finding that L-006235 attenuates weight-bearing asymmetry in the MIA model is consistent with an earlier report that 1-month administration of another cathepsin K inhibitor (AZ12606133) reduced mechanosensitivity of joint afferent fibres to non-noxious and noxious movement in the Dunkin–Hartley guinea pig model of spontaneous OA.29 In both our behavioural study and the earlier electophysiological study, the effects of the cathepsin K inhibitor were relatively slow in onset suggestive of mechanisms other than direct antinociceptive effects on the sensory nerve responses. In our study, we also assessed potential effects of L-006235 on spinal mechanisms of central sensitization, which are known to accompany the lowered hind PWTs in the MIA model. Previously, we have reported an increase in the expression of GFAP in the dorsal horn of the spinal cord,35 which is an established marker of central sensitization.9 In this study, the higher dose of L-006235 (100 mg/kg) did not significantly alter GFAP immunofluorescence in the dorsal horn of the spinal cord, suggestive of a lack of effect on at least some aspects of central sensitization that may point to a more peripheral site of action.
Cathepsin K is expressed by osteoclasts and has an essential role in bone resorption in human and mice,1 and overexpression is associated with spontaneous synovitis and cartilage degeneration.30,33 Our study of the effects of L-006235 was based on the mounting evidence of a contribution of osteoclasts to OA pain behaviour. In previous work, effects of cathepsin K inhibition on bone resorption were not associated with changes in osteoclastogenesis or survival of osteoclasts,24,28 and therefore, the effects of L-006235 on the number of osteoclasts were not quantified in this study. Comparison of the different classes of drugs, which modulate osteoclast function on pain behaviour and joint pathology in models of OA and inflammatory arthritis, highlights mechanistic differences. Unlike the bisphosphonates, cathepsin K inhibitors attenuate osteoclastic activity without altering numbers of osteoclasts and do not alter bone formation.39 Bisphosphonates have beneficial effects on joint pathology and pain behaviour in models of OA. In our previous study, effects of preventative treatment with zoledronate on pain behaviour in the MIA model were comparable in magnitude with the effects of L-006235; however, therapeutic treatment was not studied.37 Significant preventative, and reversal, effects of zoledronate on pain behaviour in MIA rats were reported in a separate study.40 The time course of the effects of zoledronate on pain behaviour was similar to those of L-006235 in this study. However, there were marked differences in terms of joint endpoints; at early time points zoledronate inhibited osteoclast-mediated cartilage resorption, and at later stages of the model treatment improved subchondral bone and cartilage integrity but not synovitis.40 The bisphosphonate alendronate inhibited bone resorption and had chondroprotective effects in a surgical model of OA, although pain was not analysed.13
Previously, we reported beneficial effects of a modified version of osteoprotegerin (OPG), which acts to sequester receptor activator of nuclear factor kappa-Β ligand and inhibits the number of subchondral bone osteoclasts, in the MIA model of OA pain.37 Osteoprotegerin-Fc prevented pain behaviour in the MIA model, effects accompanied by a robust inhibition in cartilage damage and synovial inflammation, and bone features of OA (osteoclast number and osteophyte score).36 The magnitude of inhibitory effects of preventative L-006235 on pain behaviour in the MIA model presented herein were comparable with the effects of OPG-Fc.37 In addition, the ability of L-006235 to halt further progression of pain behaviour in the MIA model once treatment commenced was also consistent with the therapeutic effects of OPG-Fc in this model. However, unlike OPG-Fc, L-006235 did not alter osteophyte score in the MIA model. The findings presented herein are consistent with the lack of effect of L-006235 on bone erosion in a model of inflammatory arthritis,41 which contrast the beneficial effects of OPG-Fc on this feature in the inflammatory arthritis model.34 Overall, the differences in the effects of OPG-Fc vs L-006235 on joint features in these models of 2 different types of arthritis suggest that mechanisms additional to cathepsin K also contribute to changes in joint structure.
To date, most previous studies in OA models have focused on the potential beneficial effects of cathepsin K inhibitors on cartilage pathology. In the anterior cruciate ligament transection (ACLT) model of OA in the rabbit L-006235 (50 mg/kg/d for 7 weeks from 1 week after surgery) significantly lowered urine CTX-II levels at 3 weeks after treatment, an effect maintained until the end of the study.14 After 7 weeks of L-006235 treatment, the Mankin score of joint pathology was significantly lower and bone features were improved, compared with vehicle-treated rabbits.14 Consistent with this finding, murine cathepsin K deletion had chondroprotective effects in the ACLT model of OA compared with wild-type controls; however, there were no beneficial effects on osteophyte formation.14 Positive effects of 28 day treatment with the cathepsin K inhibitor SB-553484 on cartilage damage in a canine model of OA have also been reported.6 Similarly, prophylactic and therapeutic effects of the potent and selective cathepsin K inhibitor MIV-711 on joint pathology in the rabbit ACLT and dog partial medial meniscectomy models were also recently reported.26 In the rabbit ACLT model, MIV-711 was given once daily for 7 weeks, starting 1 week after surgery (similar protocol as for in the L-006235 study above) and in the dog partial medial meniscectomy model for 28 days, starting 1 day before surgery (similar protocol as for the SB-553484 study above).26 The effects of L-006235 on histopathology in the collagen-induced arthritis model in mice were also evaluated in both prophylactic and therapeutic settings after dosing with L-006235 at 25 mg/kg/d. Both cartilage and bone damage, and clinical score, were significantly attenuated by preventative L-006235, whereas a therapeutic treatment once clinical signs of disease were established did not have significant effects.41 On the basis of these previous studies, our PK data and the engagement of L-006235 with cathepsin K reported herein, it seems that the duration of treatment, and dose used in our study (ie, up to 100 mg/kg twice daily for 28 days) was sufficient to attenuate pain behaviour but not structural changes to the joint in this model.
Our demonstration that the cathepsin K inhibitor attenuates the development, and halts established, weight-bearing asymmetry in the MIA model of OA pain supports the further investigation of the analgesic potential of this class of drugs as well as their effects on joint structure. Although our univariate analysis indicated that L-006235 altered the association between pain behaviour and synovitis, this is likely mediated by a cell type other than CD68+ or CD206+ macrophages. It is feasible that the positive effects of L-006235 on pain behaviour arise due to off-target effects. However, the inhibitory effect of L-006235 on human cathepsin S is 8 to 10 µM, and on mouse cathepsin S is 2.4 µM,32 making this an unlikely target for the doses and exposures achieved in this study. Nevertheless, the lack of potency data for rat cathepsin S means that we cannot rule out a species-specific effect of L-006235. From a mechanistic perspective, the more limited effects of L-006235 on lowering of hind PWTs in this study is not consistent with the robust inhibitory effects of cathepsin S inhibition on measures of allodynia in models of neuropathic pain.5 Overall, our novel finding that cathepsin K inhibition is analgesic in a clinically relevant model of OA pain provides evidence for a new therapeutic target for OA pain.
The authors declare no conflicts of interest.
The authors acknowledge the following people for their contributions to this article. Veronica Lidell for in vivo work, Sveinn Briem, Hongyu Ren, and Emma Ulander for bioanalytical analysis. Christina Rydergård and Susanne Sedig for biomarker analysis. Sofia Magli for her help with DAB immunohistochemistry.
This work was supported by Arthritis Research UK [Grant Numbers:18769; 20777] and a donation from Medivir.
Supplemental digital content
Supplemental digital content associated with this article can be found online at http://links.lww.com/PR9/A32.
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