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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.

SUBMITTER: Yi C

PROVIDER: S-EPMC5356343 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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

Yi Chun C Hao Ke-Yi KY Ma Ting T Lin Ye Y Ge Xi-Yuan XY Zhang Yu Y

Scientific reports 20170317

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 experiment ...[more]

PMID: 28304382

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Project description:Spatiotemporal implant-bone biomechanics and mechanoadaptive strains in peri-implant tissue are poorly understood. Physical and chemical characteristics of an implant-bone complex (IBC) were correlated in three-dimensional space (along the length and around a dental implant) to gather insights into time related integration of the implant with the cortical portion of a jaw bone in a rat. Rats (N = 9) were divided into three experimental groups with three rats per time point; 3-, 11-, and 24-day. All rats were fed crumbled hard pellets mixed with water (soft-food diet) for the first 3 days followed by a hard-food diet with intact hard-food pellets (groups of 11- and 24-day only). Biomechanics of the IBCs harvested from rats at each time point was evaluated by performing mechanical testing in situ in tandem with X-ray imaging. The effect of physical association (contact area) of a loaded implant with adapting peri-implant tissue, and resulting strain within was mapped by using digital volume correlation (DVC) technique. The IBC stiffness at respective time points was correlated with mechanical strain in peri-implant tissue. Results illustrated that IBC stiffness at 11-day was lower than that observed at 3-day. However, at 24-day, IBC stiffness recovered to that which was observed at 3-day. Correlative microscopy and spectroscopy illustrated that the lower IBC stiffness was constituted by softer and less mineralized peri-implant tissue that contained varying expressions of osteoconductive elements. Lower IBC stiffness observed at 11-day was constituted by less mineralized peri-implant tissue with osteoconductive elements that included phosphorus (P) which was co-localized with higher expression of zinc (Zn), and lower expression of calcium (Ca). Higher IBC stiffness at 24-day was constituted by mineralized peri-implant tissue with higher expressions of osteoconductive elements including Ca and P, and lower expressions of Zn. These spatiotemporal correlative maps of peri-implant tissue architecture, heterogeneous distribution of mineral density, and elemental colocalization underscore mechanoadaptive physicochemical properties of peri-implant tissue that facilitate functional osseointegration of an implant. These results provided insights into 1) plausible "prescription" of mechanical loads as an osteoinductive "therapeutic dose" to encourage osteoconductive elements in the peri-implant tissue that would facilitate functional osseointegration of the implant; 2) a "critical temporal window" between 3 and 11 days, and perhaps it is this acute phase during which key candidate regenerative molecules can be harnessed to accelerate osseointegration of an implant under load.

Project description:BackgroundTitanium (Ti) is now widely used as implant material due to its excellent mechanical properties and superior biocompatibilities, while its inert bioactivities might lead to insufficient osseointegration, and limit its performance in dental applications.MethodsWe introduced a robust and simple approach of modifying titanium surfaces with polysaccharide complexes. Titanium samples were subjected to hydrothermal treatment to create a uniform porous structure on the surface, followed by coating with a bioinspired and self-assembly polydopamine layer. Strontium Eucommia Ulmoides Polysaccharide (EUP-Sr) complexes are then introduced to the polydopamine-coated porous titanium. Multiple morphological and physiochemical characterizations are employed for material evaluation, while cell proliferation and gene expression tests using macrophages, primary alveolar bone osteoblasts, and vascular endothelial cells are used to provide an overall insight into the functions of the product. The significances of statistical differences were analyzed using student's t-test.ResultsMicroscopic and spectrometric characterizations confirmed that the Ti surface formed a porous structure with an adequate amount of EUP-Sr loading. The attachment was attributed to hydrogen bonding between the ubiquitous glycosidic linkage of the polysaccharide complex and the ring structure of polydopamine, yet the loaded EUP-Sr complex can be gradually released, consequently benefiting the neighboring microenvironment. Cell experiments showed no cytotoxicity of the material, and the product showed promising anti-inflammation, osseointegration, and angiogenesis properties, which were further confirmed by in vivo evaluations.ConclusionWe believe the EUP-Sr modified titanium implant is a promising candidate to be used in dental applications with notable osteoimmunomodulation and angiogenesis functions. And the novel technique proposed in this study would benefit the modification of metal/inorganic surfaces with polysaccharides for future research.

Dataset Information

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

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

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