Inhibition of cathepsin K promotes osseointegration of titanium implants in ovariectomised rats

Abstract

The bone mineral deficiency in osteoporosis poses a threat to the long-term outcomes of endosseous implants. The inhibitors of cathepsin K (CatK) significantly affect bone turnover, bone mineral density (BMD) and bone strength in the patients with osteoporosis. Therefore, we hypothesised that the application of a CatK inhibitor (CatKI) could increase the osseointegration of endosseous implants under osteoporotic conditions. Odanacatib (ODN), a highly selective CatKI, was chosen as the experimental drug. Sixteen rats were randomised into 4 groups: sham, ovariectomy (OVX) with vehicle, OVX with low-dose ODN (5 mg/kg) and OVX with high-dose ODN (30 mg/kg). Titanium implants were placed into the distal metaphysis of bilateral femurs of each OVX rat. After 8 weeks of gavaging, CatKI treatment increased the removal torque, BMD and bone-to-implant contact (BIC). Moreover, high-dose CatKI exerted a better influence than low-dose CatKI. Furthermore, CatKI treatment not only robustly suppressed CatK gene (CTSK) expression, but also moderately reduced expression of the osteoblast-related genes Runx2, Collagen-1, BSP, Osterix, OPN, SPP1 and ALP. Thus, CatKI could affect the osteoblast-related genes, although the balance of bone turnover was achieved mainly by CatK inhibition. In conclusion, CatKI prevented bone loss and aided endosseous implantation in osteoporotic conditions.

Simple 3,4-Dihydroxy-L-Phenylalanine Surface Modification Enhances Titanium Implant Osseointegration in Ovariectomized Rats

“…After micro-CT scanning, the femurs were dehydrated in an ascending ethanol series, and then processed for ground sectioning along the implant axis using Exakt Cutting and Grinding equipment (Exact Apparatebau, Norderstedt, Germany) 39 . After Levai-Laczko staining, the percentage of bone to implant contact (BIC) on the lateral side was calculated using a Bioquant Osteo Bone Biology Research System (BIOQUANT Image Analysis Corporation, Nashville, TN, USA); BIC was calculated as the length ratio of bone surface in direct contact with intra-bony implant surface 40 .…”

Advances in Osteoporotic Bone Tissue Engineering

“…Surgery is the main treatment strategy, but poor results are obtained because of various biological and surgical factors, which makes it hard to achieve a stable fixation and the failure risk (refracturation) following surgery is significant [ 5 , 20 ]. Treating osteoporotic fractures is difficult because of the reduced healing capacity, which correlates for osteoporotic patients with a far higher (~50%) failure rate of implant fixation than against non-osteoporotic patients [ 67 ], making their implants prone to pull out and failure [ 7 ], as osseointegration is inhibited by osteoporosis [ 71 ]. Decreased bone mass [ 69 ], porous structure and low strength are linked to a reduced supporting ability of an implant [ 20 ].…”

“…Authorized treatment by FDA for osteoporosis includes the bisphosphonates (alendronate, risedronate and zoledronic acid), the more recent anti-resorptive antibody denosumab and the anabolic agent teriparatide. Bisphosphonates have been connected to bone osteonecrosis [ 71 ]. Ibandronate is also available, while strontium ranelate is approved to be used in over 70 countries but not approved by the FDA [ 6 ].…”

“…Osteoclasts perform bone degradation trough acid secretion in order to demineralize HA and lysosomal cysteine protease secretion (CatK) in order to degrade the bone matrix proteins. Odanacatib does not alter normal differentiation, migration and polarization of osteoclasts [ 71 ].…”

Editorial: Tumor Necrosis Factor–Transgenic Mice: Close Enough to Human Epigenetics?

“…Here, WNT16 maintained the balance of the canonical Wnt signaling and prevented its excessive activation, thereby supporting the homeostasis of progenitor cells . LECT1 , which encodes chondromodulin I, is known to be involved in angiogenesis and suppression of T cell responses , and SP7 (osterix) takes part in adequate osteoblast function . The latter molecule also closes the fibroblast–epigenetic circle, as microRNA‐146a (miR‐146a) was found to be expressed by RA synovial fibroblasts , and a miR‐146 inhibitor strongly enhanced bone regeneration with higher expression levels of SMAD4 , RUNX2 , and osterix in newly formed bone .…”