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Wear particle-induced osteoclast over-activation is a major contributor to periprosthetic osteolysis and aseptic loosening, which can cause pathological bone loss and destruction. Hence, inhibiting excessive osteoclast-resorbing activity is an important strategy for preventing periprosthetic osteolysis. Formononetin (FMN) has been shown to have protective effects against osteoporosis, but no previous study has evaluated the effects of FMN on wear particle-induced osteolysis. In this study, we found that FMN alleviated CoCrMo alloy particles (CoPs)-induced bone loss in vivo and inhibited the formation and bone-resorptive function of osteoclasts in vitro. Moreover, we revealed that FMN exerted inhibitory effects on the expression of osteoclast-specific genes via the classical NF-κB and MAPK signaling pathways in vitro. Collectively, FMN is a potential therapeutic agent for the prevention and treatment of periprosthetic osteolysis and other osteolytic bone diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Impaired osteoblast function is involved in osteoporosis, and microRNA (miRNA) dysregulation may cause abnormal osteoblast osteogenic activity. However, the influence of miRNA on osteoblast activity and the underlying mechanisms remain elusive. In this study, miR-103-3p was found to be negatively correlated with bone formation in bone specimens from elderly women with fractures and ovariectomized (OVX) mice. Additionally, miR-103-3p directly targeted Mettl14 to inhibit osteoblast activity, and METTL14-dependent N 6 -methyladenosine (m 6 A) methylation inhibited miR-103-3p processing by the microprocessor protein DGCR8 and promoted osteoblast activity. Moreover, miR-103-3p inhibited bone formation in vivo, and therapeutic inhibition of miR-103-3p counteracted the decreased bone formation in OVX mice. Further, METTL14 was negatively correlated with miR-103-3p but positively correlated with bone formation in bone specimens from elderly women with fractures and OVX mice. Collectively, our results highlight the critical roles of the miR-103-3p/METTL14/m 6 A signaling axis in osteoblast activity, identifying this axis as a potential target for ameliorating osteoporosis., (© 2021 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

The human gut microbiota has been proven to have great effects on the regulation of bone health. However, the association between gut microbiota and particle-induced osteolysis, which is the primary cause of aseptic loosening, is still unknown. In this study, we used a combination of wide-spectrum antibiotics to eliminate the majority of gut microbiota and found that reduction of gut commensal bacteria significantly alleviated the progression of osteolysis, in which anaerobe was the biggest culprit in the exacerbation of osteolysis. Furthermore, colonization of enteropathogenic Escherichia coli (EPEC), a subspecies of anaerobe, could promote the development of particle-induced osteolysis by increasing the secretion of peripheral 5-hydroxytryptamine (5-HT) from the colon. Elevated 5-HT level decreased the phosphorylation of CREB and inhibited the proliferation of osteoblasts. Collectively, these results indicated EPEC colonization suppressed the bone formation and aggravated particle-induced osteolysis in vivo. Thus, clearance of EPEC is expected to become a potential preventive approach to treat debris-induced osteolysis and aseptic loosening. [ABSTRACT FROM AUTHOR]

Macrophage apoptosis in interface membrane, which occurs through either death receptor, mitochondrion, or endoplasmic reticulum ( ER) stress pathways, has been suggested to play an important role in promoting osteolysis. However, how and why macrophage apoptosis originates and the correlation among these apoptotic pathways is not yet clear. The objective of this study was to identify the apoptotic mechanism of macrophages, and to explore the relationship between the apoptotic pathways and progression of osteolysis. Transmission electron microscopy ( TEM) was utilized to analyze the tissue ultrastructure of wear particles, and in situ apoptotic macrophage identification was performed by TUNEL staining. We analyzed the expression of the key biomarkers of apoptotic pathways via immunohistochemistry and Western blotting. Our results demonstrated that the majority of wear particles within osteolytic interface membrane was in the 30-60 nm range, and that macrophage apoptotic ratio increased along with osteolysis progression. Normal hip dysplasia and mechanical loosening of tissues showed low expression levels of biomarkers for ER stress (Ca2+, JNK, cleaved Caspase-4, IRE1-α, Grp78/Bip, and CHOP), mitochondrion (Bcl-2, Bax, and Cytochrome c), and death receptor (Fas and cleaved Caspase-8) pathways, while osteolytic interface membrane tissues expressed high levels of these biomarkers. In addition, we found that the ER stress intensity was in complete conformity with mitochondrial dysfunction and was consistent with the results of death receptor activation. Thus, our findings suggested that wear particles generated at implant interface can accelerate macrophage apoptosis through changes in apoptotic pathways and ultimately aggravate the symptom of osteolysis. These data represent a preferential apoptotic signaling pathway of macrophages as specific target points for the prevention and therapeutic modulation of periprosthetic osteolysis. [ABSTRACT FROM AUTHOR]

ABSTRACT Wear particle-induced osteolysis is a major cause of aseptic loosening, which is one of the most common reasons for total hip arthroplasty (THA) failure. Previous studies have shown that the expression of Receptor activation of nuclear factor (NF)-kB (RANKL) by fibroblasts in periprosthetic membrane played a crucial role in wear particle-induced osteolysis. However, the underlying mechanism of RANKL expression remains largely unknown. In the present study, we investigated the effect of TiAl6V4 particle (TiPs)-induced XBP1s (spliced form of X-box binding protein 1) on RANKL expression and osteoclastogenesis both in vitro and in vivo. The levels of XBP1s in peri-implant membrane, animal models, and TiPs-stimulated fibroblasts were determined by western blots. To assess the effect of XBP1s on RANKL expression, fibroblasts were treated with both a small interfering RNA (siRNA) and an inhibitor of XBP1 prior to exposure to TiPs. The effect of XBP1s on osteoclasts formation was determined by tartrate-resistant acid phosphatase (TRAP) staining in vitro osteoclastogenesis assay and in animal models. The resorption of bone was assessed by micro-computed tomography (micro-CT) with three-dimensional reconstruction. Our results demonstrated that XBP1s was activated in periprosthetic membrane, mouse calvaria models, and TiPs-stimulated human synovial fibroblasts. Further, inhibition of XBP1s decreased the expression of RANKL and osteoclasts formation in vitro. In mouse calvaria models, both of the osteoclastogenesis and osteolysis were inhibited XBP1s inhibitor. Our results suggested that XBP1s mediated TiPs-induced of RANKL expression in fibroblasts, and down regulating XBP1s may represent a potential therapy for wear particle-induced osteolysis. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:752-759, 2017. [ABSTRACT FROM AUTHOR]

Aseptic loosening secondary to periprosthetic inflammatory osteolysis results from the biological response to wear particles and is a leading cause of arthroplasty failure. The origin of this inflammatory response remains unclear. We aim to validate the definite link between endoplasmic reticulum (ER) stress and particle-induced inflammatory signaling pathways in periprosthetic osteolysis. We examine the histopathologic changes of osteolysis and the expression of specific biomarkers for ER-stress-mediated inflammatory signaling pathways (IRE1α, GRP78/Bip, c-Fos, NF-κB, ROS and Ca). Moreover, pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) and osteoclastogenic molecules (VEGF, OPG, RANKL and M-CSF) were assessed in clinical interface membranes and murine periosteum tissues. We found wear particles to be capable of inducing ER stress in macrophages within clinical osteolytic interface membranes and murine osteolytic periosteum tissues and to be associated with the inflammatory response and osteoclastogenesis. Blocking ER stress with sodium 4-phenylbutyrate (4-PBA) results in a dramatic amelioration of particle-induced osteolysis and a significant reduction of ER-stress intensity. Simultaneously, this ER-stress blocker also lessens inflammatory cell infiltration, diminishes the capability of osteoclastogenesis and reduces the inflammatory response by lowering IRE1α, GRP78/Bip, c-Fos, NF-κB, ROS and Ca levels. Thus, ER stress plays an important role in particle-induced inflammatory osteolysis and osteoclastogenic reactions. The pharmacological targeting of ER-stress-mediated inflammatory signaling pathways might be an appealing approach for alleviating or preventing particle-induced osteolysis in at-risk patients. [ABSTRACT FROM AUTHOR]

Particle-induced osteolysis is a major cause of aseptic loosening, which is the most common reason for total hip arthroplasty (THA) failure and revision surgery. Although existing studies suggest that synovial fibroblasts present in the interfacial membrane are important targets of wear particles during bone resorption, the interaction mechanisms between the particles and fibroblasts remains elusive. In the present study, we investigated the effect of ER stress induced by CoCrMo particles (CoPs) in fibroblasts, calvarial resorption animal models and aseptic loosening clinical samples and its role in the stimulation of the RANKL expression. Our study further demonstrated that CoPs could induce significant ER stress in fibroblasts. Blocking ER stress with a specific inhibitor dramatically reduced the particle-induced expression of RANKL in vitro and in vivo . Furthermore, in fibroblasts, downregulation of the expression of XBP1s, a signaling molecule of ER stress, significantly reduced the expression of RANKL induced by wear particles. Moreover, inhibition of ER stress or XBP1s both ameliorated the CoPs-induced osteolysis in animal models. Collectively, these results suggested that in particle-induced osteolysis, CoPs could stimulate fibroblasts to secret RANKL through ER stress and the signaling molecule XBP1s. Therefore, downregulating ER stress or the signaling molecule XBP1s of fibroblasts represents a potential therapeutic approach for treating particle-induced peri-implant osteolysis. Statement of Significance For the first time, our study demonstrated that ER stress mediated the induction of RANKL expression by CoPs in fibroblasts and promoted particle-induced osteolysis. Furthermore, the upregulation of RANKL by CoPs in fibroblasts was mediated by the ER stress signaling molecule XBP1s. Both blocking ER stress and inhibiting the protein XBP1s by specific inhibitors resulted in downregulation of the expression of RANKL and amelioration of osteolysis induced by the implanted particles. Collectively, these findings suggest a possible mechanism underlying the RANKL expression induced by wear particles in fibroblasts, and downregulating ER stress and the XBP1s expression of fibroblasts represents a potential therapeutic approach for treating aseptic loosening. [ABSTRACT FROM AUTHOR]

Wear particle-induced osteolysis is a major cause of aseptic loosening, which is one of the most common reasons for total hip arthroplasty (THA) failure. Previous studies have shown that the synovial fibroblasts present in the periprosthetic membrane are important targets of wear debris during osteolysis. However, the interaction mechanisms between the wear debris and fibroblasts remain largely unknown. In the present study, we investigated the effect of ER (endoplasmic reticulum) stress induced by TiAl6V4 particles (TiPs) in human synovial fibroblasts and calvarial resorption animal models. The expression of ER stress markers, including IRE1-α, GRP78/Bip and CHOP, were determined by western blot in fibroblasts that had been treated with TiPs for various times and concentration. To address whether ER stress was involved in the expression of RANKL, the effects of ER stress blockers (including 4-PBA and TUDCA) on the expression of RANKL in TiPs-treated fibroblasts were examined by real-time PCR, western blot and ELISA. Osteoclastogenesis was assessed by tartrate resistant acid phosphatase (TRAP) staining. Our study demonstrated that ER stress markers were markedly upregulated in TiPs-treated fibroblasts. Blocking ER stress significantly reduced the TiPs-induced expression of RANKL both in vitro and in vivo. Moreover, the inhibition of ER stress ameliorated wear particle-induced osteolysis in animal models. Taken together, these results suggested that the expression of RANKL induced by TiPs was mediated by ER stress in fibroblasts. Therefore, down regulating the ER stress of fibroblasts represents a potential therapeutic approach for wear particle-induced periprosthetic osteolysis. [ABSTRACT FROM AUTHOR]

The most common cause of implant failure in joint replacement is aseptic loosening due to particle-induced osteolysis. TNF-α has been shown to be one of the key factors in the process of osteoclastogenesis. Anti-TNF agents are useful in the treatment of joint inflammation related to osteolysis. This study investigated the effect of a single subcutaneous dose of an antisense oligonucleotide (ASO) on particle-induced osteolysis. We utilized the murine calvaria osteolysis model in C57BL/J6 mice. Bone resorption was measured by the toluidine blue staining. Osteoclasts were detected by tartrate resistant acid phosphatase (TRAP) staining assay and were quantified by a TRAP quantification kit. Results show that bone resorption is 0.347 ± 0.09 mm2 in mice with particle implantation, and decreased to 0.123 ± 0.05 mm2 and 0.052 ± 0.02 mm2 after ASO treatment with low and high doses, respectively. The number of osteoclasts in animal calvaria treated with ASO is reduced compared with that of untreated animals, and the quantification results indicate that about 90% of osteoclastogenesis is suppressed by the ASO. In addition, the osteoclastogenesis can be reestablished by the addition of TNF-α. In conclusion, we demonstrate that the antisense oligonucleotide targeting to TNF-α can suppress osteolysis induced by metal particles in a murine calvaria model. This new finding may be of value in the search for novel therapeutic methods for implant loosening. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 26:1114-1120, 2008 [ABSTRACT FROM AUTHOR]

Wear particle-induced inflammatory osteoclast activation is a master contributor to periprosthetic osteolysis, which can cause pathological bone loss and destruction. Hence, inhibiting inflammation and osteoclastogenesis is an important strategy for preventing wear particle-induced osteolysis. To date, there are no FDA-approved non-surgical pharmacotherapies for arresting periprosthetic osteolysis. Kaempferol (KAE), a natural flavonol abundant in many traditional Chinese herbal medicines, has been shown to have protective effects against inflammatory bone diseases such as rheumatoid arthritis, but no previous study has evaluated the effects of KAE on wear particle-induced osteolysis. The study aimed to investigate the effects of KAE on wear particle-induced inflammatory osteolysis and osteoclast activation, and further explore the underlying mechanisms. TiAl 6 V 4 metal particles (TiPs) were retrieved from the prosthesis of patients who underwent revision hip arthroplasty due to aseptic loosening. A mouse calvarial osteolysis model was used to investigate the effects of KAE on wear particle-induced inflammatory osteolysis in vivo. Primary bone marrow-derived macrophages (BMMs) were used to explore the effects of KAE on osteoclast differentiation and bone-resorbing activity as well as the underlying mechanisms in vitro. In the present study, we found that KAE alleviated wear particle-induced inflammatory bone loss in vivo and inhibited osteoclast differentiation and function in vitro. Furthermore, we revealed that KAE exerted anti-osteoclastogenic effects by downregulating JNK and p38-MAPK signaling as well as the downstream NFATc1 expression. KAE is an alternative therapeutic agent for preventing and treating periprosthetic osteolysis and aseptic loosening. [Display omitted] • KAE can alleviate wear particle-induced inflammation and bone loss. • KAE can inhibit osteoclast differentiation and bone-resorbing activity. • KAE can suppress JNK and p38-MAPK activation as well as the downstream NFATc1 expression during osteoclastogenesis. • KAE is an alternative therapeutic agent for preventing and treating aseptic loosening. [ABSTRACT FROM AUTHOR]

Osteoblast dysfunction plays a crucial role in periprosthetic osteolysis and aseptic loosening, and endoplasmic reticulum (ER) stress is recognized as an important causal factor of wear particle-induced osteolysis. However, the influence of ER stress on osteoblast activity during osteolysis and its underlying mechanisms remain elusive. This study aims to investigate whether ER stress is involved in the detrimental effects of wear particles on osteoblasts. Through our investigation, we observed elevated expression levels of ER stress and apoptosis markers in particle-stimulated bone specimens and osteoblasts. To probe further, we employed the ER stress inhibitor, 4-PBA, to treat particle-stimulated osteoblasts. The results revealed that 4-PBA effectively alleviated particle-induced osteoblast apoptosis and mitigated osteogenic reduction. Furthermore, our study revealed that wear particle-induced ER stress in osteoblasts coincided with mitochondrial damage, calcium overload, and oxidative stress, all of which were effectively alleviated by 4-PBA treatment. Encouragingly, 4-PBA administration also improved bone formation and attenuated osteolysis in a mouse calvarial model. In conclusion, our results demonstrate that ER stress plays a crucial role in mediating wear particle-induced osteoblast apoptosis and impaired osteogenic function. These findings underscore the critical involvement of ER stress in wear particle-induced osteolysis and highlight ER stress as a potential therapeutic target for ameliorating wear particle-induced osteogenic reduction and bone destruction. • The levels of ER stress and apoptosis markers are elevated in bone specimens and osteoblasts exposed to particles. • Particle-induced ER stress in osteoblasts coincide with mitochondrial damage, calcium overload, and oxidative stress. • Inhibition of ER stress through 4-PBA treatment alleviates particle-induced osteoblast apoptosis. • Inhibition of ER stress through 4-PBA treatment mitigates particle-induced osteogenic reduction. • Mitigating ER stress through 4-PBA treatment effectively eases particle-induced osteolysis and promotes bone formation. [ABSTRACT FROM AUTHOR]

Peri-prosthetic osteolysis and the consequent aseptic loosening constitute the most common reason for total joint arthroplasty failure and surgical revision. Although numerous studies suggest that pro-inflammatory cytokines induced by wear particles is involved in the pathological process of aseptic loosening, the underlying mechanism linking wear particles to pro-inflammatory cytokines remains to be illustrated. In the present study, we investigated the effect of autophagy on TNF-α secretion induced by TiAl 6 V 4 particles (TiPs) in macrophages and in a calvarial resorption animal model. Our study demonstrated that TiPs activated autophage in macrophages and particle-induced osteolysis animal models as well as periprosthetic membranes of patients with aseptic loosening. The autophagy inhibitor 3-MA (3-methyladenine) could dramatically reduce TiPs-induced TNF-α expression both in macrophages and in membranes from animal models. Furthermore, inhibition of autophagy with 3-MA ameliorated the severity of osteolysis in PIO animal models. Collectively, these results suggest that autophagy plays a key role in TiPs-induced osteolysis by promoting TNF-α expression and that blocking autophagy may represent a potential therapeutic approach for treating particle-induced peri-implant osteolysis. [ABSTRACT FROM AUTHOR]

Abstract: We hypothesized that endoplasmic reticulum (ER) stress in macrophages induced by wear particles was one of the reasons for particle-induced osteolysis (PIO) in total hip arthroplasty (THA) failure. In the present study, the expression of ER stress markers was examined by Western blot in macrophages treated with particles from materials used in prosthetics, specimens from PIO animal models and patients suffering from aseptic loosening. To address whether ER stress triggers these inflammatory responses, the effect of an ER stress blocker on the expression of inflammatory cytokines in particle-treated macrophages and PIO animal models was tested. The results demonstrated that ER stress markers were significantly upregulated in particle-treated macrophages, periosteum tissues from PIO animal models and clinical specimens of prosthesis loosening. Blocking ER stress with a specific inhibitor dramatically reduced the particle-induced expression of inflammatory cytokines in vitro and in vivo. Furthermore, in PIO animal models, this ER stress blocker dramatically suppressed the differentiation of osteoclasts and reduced the severity of osteolysis. Thus, the results of the present study suggest that ER stress plays a key role in particle-induced osteolysis and that targeting the ER stress pathway may lead to novel therapeutic approaches for the treatment of aseptic prosthesis loosening. [Copyright &y& Elsevier]