Effect of a cathepsin K inhibitor on arthritis and bone mineral density in ovariectomized rats with collagen-induced arthritis

Abstract

ObjectivesCathepsin K is expressed by osteoclasts and synovial fibroblasts and degrades key components of bone and cartilage. Inhibition of cathepsin K protease activity may be beneficial for the prevention of bone erosion and cartilage degradation in rheumatoid arthritis (RA). The collagen-induced arthritis (CIA) rat model is well established for studying the pathology and treatment of RA. We investigated the effect of ONO-KK1-300-01, a cathepsin K inhibitor (CKI), on arthritis and bone mineral density (BMD) in rats with CIA.MethodsSeven-month-old female Sprague Dawley rats were divided into 5 groups: rats without CIA (CNT); CIA rats that underwent ovariectomy (OVX) and were treated with CKI; CIA rats that underwent OVX and were treated with vehicle (Veh); CIA rats that underwent sham surgery and were treated with CKI; and CIA rats that underwent sham surgery and were treated with Veh. CKI was orally administered at a dose of 15 mg/kg, thus initiating collagen sensitization, until death at 4 weeks. We evaluated hind paw thickness and the arthritis score every week until death. Radiographs of the resected left foot were obtained with a soft X-ray apparatus. Destruction of bone and cartilage was classified and scored as previously described by Engelhardt et al. BMD was measured by bone densitometry at the halfway point between the distal metaphysis and the diaphysis of the resected right femur. We also performed histomorphometry of the proximal left tibia, histological evaluation of arthritis, and a bone strength test.ResultsCKI administration significantly reduced hind paw thickness and the arthritis score, and prevented a decrease in BMD. The radiographic score was significantly lower in the CKI group than in the Veh group. In the histomorphometric analysis, bone-resorption parameters were significantly lower in the CKI groups than in the Veh groups. CKI significantly inhibited synovial proliferation in the CIA rats. In the bone strength test, the ultimate stress was significantly higher in the CKI groups than in the Veh groups.ConclusionOur findings indicate that cathepsin K inhibitors may inhibit systemic and local bone loss, ameliorate arthritis, and attenuate the decrease of bone strength in an animal model of arthritis.

Cathepsin K deficiency promotes alveolar bone regeneration by promoting jaw bone marrow mesenchymal stem cells proliferation and differentiation via glycolysis pathway

“…15,16 So more and more studies focus on the dual regulation of CTSK on bone immunity and bone remodelling. [17][18][19] Silencing of Ctsk by AAV-RNAi was used to inhibit the development of periapical periodontitis in mice. 20 Silencing of Ctsk or inhibiting the function of CTSK by ODN was also used to inhibit inflammation and bone loss caused by periodontal diseases.…”

Cathepsin K: The Action in and Beyond Bone

“…Inhibition of CatK could suppress the cartilage degradation as well as the systemic and local bone loss to prevent joint destruction in preclinical RA models. Skoumal et al, 2005;Asagiri et al, 2008;Svelander et al, 2009;Hao et al, 2015;Yamashita et al, 2018;Yamada et al, 2019…”

“…By genetic approach, it was found that CatK deficiency largely prevented the cartilage erosion and bone destruction and reduced the joint inflammation in mice with TNF-α-mediated arthritis (Hao et al, 2015). By pharmacological approach, several preclinical studies concordantly showed that inhibition of CatK could suppress the cartilage degradation as well as the systemic and local bone loss to prevent joint destruction in preclinical RA models (Asagiri et al, 2008;Svelander et al, 2009;Yamashita et al, 2018;Yamada et al, 2019). Interestingly, the efficacy of CatK inhibition on joint inflammation are contradictory among these studies.…”

Mitochondria as Key Players in the Pathogenesis and Treatment of Rheumatoid Arthritis

“…From a functional perspective, these metabolic adaptations were linked to increased macrophage production of the collagenase cathepsin K ( 37 ). This enzyme is involved in bone resorption and contributes to joint destruction in arthritis ( 38 ). Zeisbrich et al.…”