Matrix stiffness regulates osteoclast fate through integrin-dependent mechanotransduction

Osteoclasts ubiquitously participate in bone homeostasis,and their aberration leads to bone diseases,such as osteoporosis.Current clinical strategies by biochemical signaling molecules often perturb innate bone metabolism owing to the uncontrolled management of osteoclasts.Thus,an alternative strategy of precise regulation for osteoclast differentiation is urgently needed.To this end,this study proposed an assumption that mechanic stimulation might be a potential strategy.Here,a hydrogel was created to imitate the physiological bone microenvironment,with stiffnesses ranging from 2.43kPa to 68.2kPa.The impact of matrix stiffness on osteoclast behaviors was thoroughly investigated.Results showed that matrix stiffness could be harnessed for directing osteoclast fate in vitro and in vivo.In particular,increased matrix stiffness inhibited the integrinβ3-responsive RhoA-ROCK2-YAP-related mechanotransduction and promoted osteoclastogenesis.Notably,preosteoclast development is facilitated by medium-stiffness hydrogel(M-gel)possessing the same stiffness as vessel ranging from 17.5 kPa to 44.6 kPa by partial suppression of mechanotransduction,which subsequently encouraged revascularization and bone regeneration in mice with bone defects.Our works provide an innovative approach for finely regulating osteoclast differentiation by selecting the optimum matrix stiffness and enable us further to develop a matrix stiffness-based strategy for bone tissue engineering.

Nano-needle strontium-substituted apatite coating enhances osteoporotic osseointegration through promoting osteogenesis and inhibiting osteoclastogenesis

Implant loosening remains a major clinical challenge for osteoporotic patients.This is because osteoclastic bone resorption rate is higher than osteoblastic bone formation rate in the case of osteoporosis,which results in poor bone repair.Strontium(Sr)has been widely accepted as an anti-osteoporosis element.In this study,we fabricated a series of apatite and Sr-substituted apatite coatings via electrochemical deposition under different acidic conditions.The results showed that Ca and Sr exhibited different mineralization behaviors.The main mineralization products for Ca were CaHPO4⋅2H2O and Ca3(PO4)2 with the structure changed from porous to spherical as the pH values increased.The main mineralization products for Sr were SrHPO4 and Sr5(PO4)3OH with the structure changed from flake to needle as the pH values increased.The in vitro experiment demonstrated that coatings fabricated at high pH condition with the presence of Sr were favorable to MSCs adhesion,spreading,proliferation,and osteogenic differentiation.In addition,Sr-substituted apatite coatings could evidently inhibit osteoclast differentiation and fusion.Moreover,the in vivo study indicated that nano-needle like Sr-substituted apatite coating could suppress osteoclastic activity,improve new bone formation,and enhance bone-implant integration.This study provided a new theoretical guidance for implant coating design and the fabricated Sr-substituted coating might have potential applications for osteoporotic patients.

Calcium phosphate-based materials regulate osteoclast-mediated osseointegration

Calcium phosphate-based materials(CaP)have been widely used as bone graft substitutes with a decent osseointegration.However,the mechanism whereby cells function and repair the bone defect in CaP micro-environment is still elusive.The aim of this study is to find the mechanism how osteoclast behaviors mediate bone healing with CaP scaffolds.Recent reports show that behaviors of osteoclast are closely related with osteogenesis,thus we make a hypothesis that active osteoclast behaviors induced by CaP facilitate bone healing.Here,we found a new mechanism that CaP can regulate osteoclast-mediated osseointegration.Calcium phosphate cement(CPC)is selected as a representative CaP.We demonstrate that the osteoclast-mediated osseointegration can be strongly modulated by the stimulation with CaP.An appropriate Ca/P ratio in CaP can effectively promote the RANKL-RANK binding and evoke more activated NF-κB signaling transduction,which results in vigorous osteoclast differentiation.We observe significant improvement of bone healing in vivo,owing to the active coupling effect of osteoclasts.What is more noteworthy is that the phosphate ions released from CaP can be a pivotal role regulating osteoclast activity by changing Ca/P ratio readily in materials.These studies suggest the potential of harnessing osteoclast-mediated osteogenesis in order to develop a materials-manipulated approach for improving osseointegration.

A novel snail-inspired bionic design of titanium with strontium-substituted hydroxyapatite coating for promoting osseointegration

As the population ages,more and more people are suffering from osteoarthritis(OA),resulting in an increasing requirement for joint implants.Surface modification to improve the topology and composition of the implants has been proved to be an effective way to improve the primary stability and long-term success rate of joint implants.In this work,a bionic micro/nano-structure accompanied with a strontium-substituted hydroxyapatite(SrHA)coating was fabricated on titanium(Ti)surface via electrochemical corrosion,ultrasonic treatment,and hydrothermal deposition methods.Thein vitro study demonstrated that the bionic structure and the bioactive apatite could synergistically increase the expressions of integrin-related gene(ITGα5β1)and osteoblastic genes(Col-I and OCN),and thus promote osteoblast growth.In addition,owing to the anti-bone resorption property of Sr^(2+),the coating could effectively inhibit osteoclast differentiation and proliferation.In a word,the prepared samples not only promoted osteogenesis but also inhibited osteoclastogenesis.The in vivo experiment via a rabbit model found that the bionic structured surface provided the pore for new bone ingrowth,which was beneficial to the mechanical interlocking between the implant and bone.Moreover,the bionic structure and bioactive SrHA coating had a synergistic effect on promoting bone formation,osseointegration,and bone-implant bonding strength.This study therefore presented a new strategy to fabricate bio-functionalized Ti-based implants for potential application in orthopedics field.