No Revisions Attributable To Wear of Highly Cross-Linked Polyethylene Liners: A Long Term Follow-up Study.

INTRODUCTION: There is a paucity of data beyond 15 years on the survivorship of total hip arthroplasty since the introduction of highly cross-linked polyethylene (HXLPE) liners. Our aim was to evaluate implant survivorship, liner wear rates, and clinical outcomes after primary THA using HXLPE liners implanted between 1999 and 2002. METHODS: Between 1999 and 2002, 690 primary THAs utilizing 28-mm femoral heads and HXLPE liners of a single design were identified using our institutional total joint registry. Femoral heads were made of metal in 96% of cases and ceramic in 4%. The mean age was 56 years, 48% were women, and the mean BMI was 30. Survivorship analyses were performed for the outcomes of implant revision, reoperation, and complications for the entire cohort. Linear HXLPE liner wear rates were determined on 197 hips with radiographs with more than 18.5 years of follow-up. RESULTS: At 20 years, survivorship free of revision was 94%, free of reoperation was 92%, and free of any complication was 81%. There were no documented wear-related revisions. The linear wear rate at a mean of 20.3 years postoperatively was 0.02 mm/year. There was no statistically significant difference in measured wear observed between the first available postoperative radiographs and those taken at the final follow-up. The use of elevated liners, patient BMI, age, preoperative diagnosis, acetabular component inclination, and anteversion angles were not associated with increased wear rates. Mean Harris Hip Scores improved from 52 preoperatively to 90 at greater than 18.5 years. CONCLUSIONS: Primary THAs using a single first generation HXLPE liner demonstrated excellent survivorship and clinical outcomes at long-term follow-up with no wear-related revisions. Wear rates of HXLPE liners at 20 years are exceedingly low and are not significantly impacted by acetabular component position or patient-dependent variables such as BMI. LEVEL OF EVIDENCE: IV.

3D Printed Calcium Phosphate Physiochemically Dual-Regulating Pro-Osteogenesis and Antiosteolysis for Enhancing Bone Tissue Regeneration.

Osteoblasts and osteoclasts are two of the most important types of cells in bone repair, and their bone-forming and bone-resorbing activities influence the process of bone repair. In this study, we proposed a physicochemical bidirectional regulation strategy via ration by physically utilizing hydroxyapatite nanopatterning to recruit and induce MSCs osteogenic differentiation and by chemically inhibiting osteolysis activity through the loaded zoledronate. The nanorod-like hydroxyapatite coating was fabricated via a modified hydrothermal process while the zoledronic acid was loaded through the chelation within the calcium ions. The fabrication of a hydroxyapatite/zoledronic acid composite biomaterial. This biomaterial promotes bone tissue regeneration by physically utilizing hydroxyapatite nanopatterning to recruit and induce MSCs osteogenic differentiation and by chemically inhibiting osteolysis activity through the loaded zoledronate. The nanorod-like hydroxyapatite coating was fabricated via a modified hydrothermal process while the zoledronic acid was loaded through the chelation within the calcium ions. The in vitro results tested on MSCs and RAW 246.7 indicated that the hydroxyapatite enhanced cells' physical sensing system, therefore enhancing the osteogenesis. At the same time the zoledronic acid inhibited osteolysis by downregulating the RANK-related genes. This research provides a promising strategy for enhancing bone regeneration and contributes to the field of orthopedic implants.

XAF1 promotes osteoclast apoptosis by antagonizing the XIAP-caspase axis.

Background: Over-activated osteoclast (OC) is a major cause of diseases related to bone loss and bone metabolism. Both bone resorption inhibition and apoptosis induction of osteoclast are crucial in treating these diseases. X-linked inhibitor of apoptosis protein (XIAP)-associated factor 1 (XAF1) is an important interferon-stimulated and apoptotic gene. However, how XAF1 regulates bone formation and remodeling is unknown. Methods: We generate global and chimeric Xaf1 knockout mouse models and utilize these models to explore the function and mechanism of XAF1 in regulating bone formation and remodeling in vivo and in vitro. Results: We show that XAF1 depletion enhances osteoclast generation in vitro. XAF1 knockout increases osteoclast number and bone resorption, thereby exacerbating bone loss in both OVX and osteolysis models. Activation of XAF1 with BV6 (a potent XIAP inhibitor) suppresses osteoclast formation. Mechanistically, XAF1 deletion decreases osteoclast apoptosis by facilitating the interaction between XIAP and caspase-3/7. Conclusions: Our data illustrates an essential role of XAF1 in controlling osteoclastogenesis in both osteoporosis and osteolysis mouse models and highlights its underlying mechanism, indicating a potential role in clinical treatment.The translational potential of this article: The translation potential of this article is that we first indicated that osteoclast apoptosis induced by XAF1 contribute to the progression of osteoporosis and osteolysis, which provides a novel strategy in the prevention of osteoporosis and osteolysis.

Homozygosity for a Rare Plec Variant Suggests a Contributory Role in Congenital Insensitivity to Pain.

Congenital insensitivity to pain is a rare human condition in which affected individuals do not experience pain throughout their lives. This study aimed to identify the molecular etiology of congenital insensitivity to pain in two Thai patients. Clinical, radiographic, histopathologic, immunohistochemical, and molecular studies were performed. Patients were found to have congenital insensitivity to pain, self-mutilation, acro-osteolysis, cornea scars, reduced temperature sensation, tooth agenesis, root maldevelopment, and underdeveloped maxilla and mandible. The skin biopsies revealed fewer axons, decreased vimentin expression, and absent neurofilament expression, indicating lack of dermal nerves. Whole exome and Sanger sequencing identified a rare homozygous variant c.4039C>T; p.Arg1347Cys in the plakin domain of Plec, a cytolinker protein. This p.Arg1347Cys variant is in the spectrin repeat 9 region of the plakin domain, a region not previously found to harbor pathogenic missense variants in other plectinopathies. The substitution with a cysteine is expected to decrease the stability of the spectrin repeat 9 unit of the plakin domain. Whole mount in situ hybridization and an immunohistochemical study suggested that Plec is important for the development of maxilla and mandible, cornea, and distal phalanges. Additionally, the presence of dental anomalies in these patients further supports the potential involvement of Plec in tooth development. This is the first report showing the association between the Plec variant and congenital insensitivity to pain in humans.

Hecogenin alleviates LPS-induced osteolysis via regulating pyroptosis and ROS involved Nrf2 activation.

Reactive oxidative species (ROS) generation triggers pyroptosis and induces development of inflammatory osteolysis. Hecogenin (HG) has anti-inflammatory and antioxidative property, but its effects on inflammatory osteolysis remains unclear. In our study, we investigated the mechanism of HG on pyroptosis and its effect on inflammatory osteolysis in vitro and in vivo. The impact of HG on osteoclastogenesis was evaluated using cytotoxicity, TRAcP staining and bone resorption assays. The RNA-sequencing was employed to identify potential signaling pathways, and then RT-qPCR, western blot, immunofluorescence, and ELISA were used to verify. To determine the protective effect of HG in vivo, Lipopolysaccharide (LPS)-induced animal models were utilized, along with micro-CT and histological examination. HG suppressed RANKL-induced osteoclast differentiation, bone resorption, NFATc1 activity and downstream factors. RNA-sequencing results showed that HG inhibited osteoclastogenesis by modulating the inflammatory response and macrophage polarization. Furthermore, HG inhibited the NF-κB pathway, and deactivated the NLRP3 inflammasome. HG activated the expression of nuclear factor E2-related factor 2 (Nrf2) to eliminate ROS generation. Importantly, the inhibitory effect of HG on NLRP3 inflammasome could be reversed by treatment with the Nrf2 inhibitor ML385. In vivo, HG prevented the mice against LPS-induced osteolysis by suppressing osteoclastogenesis and inflammatory factors. In conclusion, HG could activate Nrf2 to eliminate ROS generation, inactivate NLRP3 inflammasome and inhibit pyroptosis, thereby suppressing osteoclastogenesis in vitro and alleviating inflammatory osteolysis in vivo, which indicating that HG might be a promising candidate to treat inflammatory osteolysis.

Engineered Niobium Carbide MXenzyme-Integrated Self-Adaptive Coatings Inhibiting Periprosthetic Osteolysis by Orchestrating Osteogenesis-Osteoclastogenesis Balance.

Periprosthetic osteolysis induced by the ultrahigh-molecular-weight polyethylene (UHMWPE) wear particles is a major complication associated with the sustained service of artificial joint prostheses and often necessitates revision surgery. Therefore, a smart implant with direct prevention and repair abilities is urgently developed to avoid painful revision surgery. Herein, we fabricate a phosphatidylserine- and polyethylenimine-engineered niobium carbide (Nb2C) MXenzyme-coated micro/nanostructured titanium implant (PPN@MNTi) that inhibits UHMWPE particle-induced periprosthetic osteolysis. The specific mechanism by which PPN@MNTi operates involves the bioresponsive release of nanosheets from the MNTi substrate within an osteolysis microenvironment, initiated by the cleavage of a thioketal-dopamine molecule sensitive to reactive oxygen species (ROS). Subsequently, functionalized Nb2C MXenzyme could target macrophages and escape from lysosomes, effectively scavenging intracellular ROS through its antioxidant nanozyme-mimicking activities. This further achieves the suppression of osteoclastogenesis by inhibiting NF-κB/MAPK and autophagy signaling pathways. Simultaneously, based on the synergistic effect of MXenzyme-integrated coatings and micro/nanostructured topography, the designed implant promotes the osteogenic differentiation of bone mesenchymal stem cells to regulate bone homeostasis, further achieving advanced osseointegration and alleviable periprosthetic osteolysis in vivo. This study provides a precise prevention and repair strategy of periprosthetic osteolysis, offering a paradigm for the development of smart orthopedic implants.

Clinical Results and CT Analysis of ISA Stemless at a Minimum Follow-up of 2 Years.

INTRODUCTION: The utilization of stemless anatomic total shoulder arthroplasty is on the rise. Epiphyseal fixation leads to radiological bone remodeling, which has been reported to exceed 40% in certain studies series. The aim of this study was to present the clinical and radiological outcomes of a stemless implant with asymmetric central epiphyseal fixation at an average follow-up of 31 months. MATERIALS: This retrospective multicenter study examined prospective data of patients undergoing total anatomic arthroplasty with ISA Stemless implant and followed up at least 2 years. Clinical assessment included preoperative and final follow-up measurements of active range of motion (ROM), Constant score, and Subjective Shoulder Value (SSV). Anatomical epiphyseal reconstruction and bone remodeling at the 2-year follow-up were assessed by standardized Computed Tomography Scanner (CT scan). Statistical analysis employed unpaired Student's t-test or chi-squared test depending on the variable type, conducted using EasyMedStat software (version 3.22; www.easymedstat.com). RESULTS: Fifty patients (mean age 68 years, 62% females) were enrolled, with an average follow-up of 31 months (24-44). Primary osteoarthritis (68%) with type A glenoid (78%) was the prevailing indication. The mean Constant score and SSV improved significantly from 38 ± 11 to 76 ± 11 (p<0.001) and from 31% ± 16 to 88% ± 15 (p<0.001) respectively at the last follow-up. Forward elevation, external rotation and internal rotation ROM increased by 39° ± 42, 28° ± 21 and 3,2 ± 2,5 points respectively, surpassing the Minimally Clinically Important Difference (MCID) after total shoulder arthroplasty. No revisions were necessary. CT scans identified 30% osteolysis in the posterior-medial calcar region, devoid of clinical repercussions. No risk factors were associated with bone osteolysis. CONCLUSION: At an average follow-up of 31 months, ISA Stemless implant provided favorable clinical results. CT analysis revealed osteolysis-like remodeling in the posterior-medial zone of the calcar (30%), without decline in clinical outcomes and revisions. Long-term follow-up studies are mandated to evaluate whether osteolysis is associated with negative consequences.

diABZI and poly(I:C) inhibit osteoclastic bone resorption by inducing IRF7 and IFIT3.

Type I interferons (IFN-I) are pleiotropic factors endowed with multiple activities that play important roles in innate and adaptive immunity. Although many studies indicate IFN-I inducers exert favorable effects on broad-spectrum antivirus, immunomodulation, and anti-tumor by inducing endogenous IFN-I and IFN-stimulated genes (ISGs), their function in bone homeostasis still needs further exploration. Here, our study demonstrates two distinct IFN-I inducers, diABZI and poly(I:C), as potential therapeutics to alleviate osteolysis and osteoporosis. Firstly, IFN-I inducers suppress the genes that control osteoclast (OC) differentiation and activity in vitro. Moreover, diABZI alleviates bone loss in Ti particle-induced osteolysis and ovariectomized (OVX)-induced osteoporosis in vivo by inhibiting OC differentiation and function. In addition, the inhibitory effects of IFN-I inducers on OC differentiation are not observed in macrophages derived from Ifnar1-/- mice, which indicate that the suppressive effect of IFN-I inducers on OC is IFNAR-dependent. Mechanistically, RNAi-mediated silencing of IRF7 and IFIT3 in OC precursors impair the suppressive effect of the IFN-I inducers on OC differentiation. Taken together, these results demonstrate that IFN-I inducers play a protective role in bone turnover by limiting osteoclastogenesis and bone resorption through the induction of OC-specific mediators via the IFN-ß signaling pathway.

The Measurement of the Oxidative Index of Polyethylene Obtained during Revision Hip Arthroplasty and Assessment of Its Variability Depending on the Degree of Osteolysis, Implantation Time, as Well as the Size and Material of the Utilized Head.

Background/Objectives: Aseptic loosening is the leading cause of late revision in total hip arthroplasty, primarily due to degenerative oxidation of polyethylene components, leading to wear particle formation and periacetabular osteolysis. This study aimed to analyze the oxidation levels in polyethylene liners and cemented cups retrieved from revision surgeries using Fourier-transform infrared spectroscopy (FTIR) and to explore the correlation between oxidation levels and factors such as head size, head material, fixation method, and implant survival time. Methods: Polyethylene liners and cups were analyzed post-revision surgery to assess oxidation levels, which were then compared to periacetabular bone loss measured by the Paprosky classification. This study evaluated the impact of head size (28 mm vs. 32 mm), head material (ceramic vs. metal), and fixation methods on oxidation. The relationship between the mean oxidation index (OI) and implant survival time was also investigated. Results: There was a significant positive correlation between the mean oxidation index of the polyethylene components and the severity of periacetabular osteolysis according to the Paprosky scale. While the mean OI for samples articulating with ceramic heads was lower than for those with metal heads, and the mean OI for samples with a 32 mm head size was lower than for those with a 28 mm size, these differences were not statistically significant. Furthermore, the fixation method did not affect the oxidation index, and no correlation was found between OI and the survival time of the implants. Conclusions: This study confirms a direct correlation between polyethylene oxidation and periacetabular osteolysis in hip replacements, highlighting the importance of material choice and design in potentially reducing the risk of aseptic loosening. Despite the lack of significant differences in oxidation levels based on head material and size, these factors may still play a role in the long-term outcome of hip arthroplasty, warranting further investigation.

Influence of metallic particles and TNF on the transcriptional regulation of NLRP3 inflammasome-associated genes in human osteoblasts.

Introduction: The release of mature interleukin (IL-) 1ß from osteoblasts in response to danger signals is tightly regulated by the nucleotide-binding oligomerization domain leucine-rich repeat and pyrin-containing protein 3 (NLRP3) inflammasome. These danger signals include wear products resulting from aseptic loosening of joint arthroplasty. However, inflammasome activation requires two different signals: a nuclear factor-kappa B (NF-κB)-activating priming signal and an actual inflammasome-activating signal. Since human osteoblasts react to wear particles via Toll-like receptors (TLR), particles may represent an inflammasome activator that can induce both signals. Methods: Temporal gene expression profiles of TLRs and associated intracellular signaling pathways were determined to investigate the period when human osteoblasts take up metallic wear particles after initial contact and initiate a molecular response. For this purpose, human osteoblasts were treated with metallic particles derived from cobalt-chromium alloy (CoCr), lipopolysaccharides (LPS), and tumor necrosis factor-alpha (TNF) alone or in combination for incubation times ranging from one hour to three days. Shortly after adding the particles, their uptake was observed by the change in cell morphology and spectral data. Results: Exposure of osteoblasts to particles alone increased NLRP3 inflammasome-associated genes. The response was not significantly enhanced when cells were treated with CoCr + LPS or CoCr + TNF, whereas inflammation markers were induced. Despite an increase in genes related to the NLRP3 inflammasome, the release of IL-1ß was unaffected after contact with CoCr particles. Discussion: Although CoCr particles affect the expression of NLRP3 inflammasome-associated genes, a single stimulus was not sufficient to prime and activate the inflammasome. TNF was able to prime the NLRP3 inflammasome of human osteoblasts.

Artemisinic acid attenuates osteoclast formation and titanium particle-induced osteolysis via inhibition of RANKL-induced ROS accumulation and MAPK and NF-κB signaling pathways.

Periprosthetic osteolysis (PPO) is the most common cause of joint arthroplasty failure. Its progression involves both biological and mechanical factors. Osteoclastogenesis induced by wear from debris-cell interactions, ultimately leading to excessive bone erosion, is considered the primary cause of PPO; therefore, targeting osteoclasts is a promising treatment approach. Currently available drugs have various side effects and limitations. Artemisinic acid (ArA) is a sesquiterpene isolated from the traditional herb Artemisia annua L. that has various pharmacological effects, such as antimalarial, anti-inflammatory, and antioxidant activities. Therefore, this study was aimed at investigating the effect of ArA on osteoclast formation and bone resorption function in vitro, as well as wear particle-induced osteolysis in vivo, and to explore its molecular mechanism of action. Here, we report that ArA inhibits RANKL-stimulated osteoclast formation and function. Mechanistically, ArA suppresses intracellular reactive oxygen species levels by activating the antioxidant response via nuclear factor erythroid-2-related factor 2 (Nrf2) pathway upregulation. It also inhibits the mitogen-activated kinases (MAPK) and nuclear factor-κB (NF-κB) pathways, as well as the transcription and expression of NFATc1 and c-Fos. In vivo experiments demonstrated that ArA reduces osteoclast formation and alleviates titanium particle-induced calvarial osteolysis. Collectively, our study highlights that ArA, with its osteoprotective and antioxidant effects, is a promising therapeutic agent for preventing and treating PPO and other osteoclast-mediated osteolytic diseases.

Long-Term Outcomes of Wrist Arthroplasty Using the ReMotion™ Implant in Non-inflammatory Wrist Pathology.

Background: Wrist arthroplasty is increasingly offered to patients with symptomatic wrist arthritis as an alternative to wrist arthrodesis. The purpose of this study was to present our outcomes with the ReMotion™ wrist arthroplasty in a consecutive series of patients with wrist arthritis from non-inflammatory conditions. Methods: Thirteen (eight women, nine dominant wrists) patients, 68 (44-85) years of age with advanced radiocarpal arthritis due to SLAC/SNAC (11) and Kienbock disease (2) had a ReMotion™ (Stryker, Michigan, USA) wrist arthroplasty implanted, and were prospectively followed for 7 (4-9) years. The outcome measures included patient-rated wrist and hand evaluation (PRWHE) score, disabilities of the arm, shoulder and hand questionnaire (QuickDASH) score, visual analogue pain score (0-10) on the radial and ulnar aspect of the wrist at rest (VASrR/VASuR) and activity (VASrA/VASuA), active wrist range of motion (AROM) including flexion, extension, ulnar and radial deviation, pronation and supination and grip and key-pinch strength measured preoperatively and at yearly follow-ups by independent hand therapists. Results: Six patients had ten re-operations during the follow-up including four revisions to a new arthroplasty. Four were considered loose at follow-up. A significant reduction in PRWHE (63 to 12), radial pain at activity (6 to 1) and increased pronation (85° v 90°) was observed. Conclusions: We found a high complication and reoperation rate, two out of 13 had no complications or reoperations. The ReMotion™ arthroplasty should be used with caution in non-inflammatory wrist patients and the patients followed closely. A high reoperation and revision rate can be expected, and surgeons familiar with revision arthroplasty procedures should perform the surgery. Level of Evidence: Level II (Therapeutic).

Inverted-Bearing Reverse Shoulder Arthroplasty: Long-term Survivorship, Complications, Clinical and Radiological Outcomes.

BACKGROUND: Inverted-bearing reverse shoulder arthroplasty (IB-RSA) is characterized by a polyethylene glenosphere and a metallic humeral liner to minimize PE wear and debris secondary to impingement between the humerus and glenoid neck. IB-RSA long-term survivorship, complication and revision rates, as well as clinical and radiographic outcomes have not been reported yet. METHODS: This is a monocentric retrospective study on a consecutive series of 151 patients who underwent primary IB-RSA from January 2009 to September 2015 and were evaluated clinically and radiologically at minimum 8 years follow-up. All complications and reoperations were recorded. Survivorship analysis with any revision surgery as endpoint was done using Kaplan-Meier survival curves. RESULTS: Seventy-eight patients (follow-up rate 51.7%) were reviewed at a mean follow-up of 10.1 ± 1.9 years. At 10 years the revision-free survival was 98.7% (95% CI: 94.8-99.7). Sixteen complications (10.6%) were observed: 2 axillary nerve injuries, 2 infections, 2 glenoid loosenings (which stabilized within one year), 2 cases of otherwise unexplained painful stiffness, 4 acromial fractures, 1 post-traumatic scapular pillar fracture and 3 post-traumatic humeral periprosthetic fractures. Two patients were revised due to infection. No cases of late glenoid loosening and humeral loosening were observed. The revision rate was 1.3%. All the clinical scores and range of motion significantly improved at the last follow-up compared with preoperative status: final Constant score was 66.1 ± 17.4, SSV 79.1 ± 20.9, ASES 82.2 ± 17.7. Scapular notching was observed in 51.4% of patients: only 1 case of grade 3 notching was observed in an early glenoid subsidence case. CONCLUSIONS: Primary IB-RSA appears to be a safe and effective procedure and does not present specific implant-associated complications at long-term follow-up. Radiographic analysis showed that inverting the biomaterials leads to a distinct kind of notching with mainly mechanical features.

A case report of chronic intermedullary inflammation of bone in a child.

Osteolytic lesions refer to the destruction of any part of bone due to a disease process (pertaining to dissolution of bone, especially loss of calcium). Osteomyelitis is the inflammation of the bone caused by an infecting organism. Although bone is normally resilient to bacterial colonization, events such as trauma, surgery, infections, the presence of foreign bodies, and anemia may disrupt bony integrity and lead to the onset of bone infections. Sometimes, osteomyelitis causes no signs and symptoms or the signs and symptoms are hard to distinguish from other problems. This may be true for children, older adults, and people whose immune systems are compromised. Here, we report a case of chronic intermedullary inflammation of bone in a child.

Giant Pseudotumour Following Ceramic on Polyethylene Total Hip Replacement.

Introduction: Metal reaction and pseudotumor formation are very rare complications following ceramic on polyethylene total hip replacement. Pseudotumors have been described in the case of metal on polyethylene as well as in metal on ceramic interfaces. We report the largest pseudotumor formation to be observed after a thorough literature review following ceramic on polyethylene total hip replacement in a case of ankylosing spondylitis and chronic kidney disease. Case report: The patient had reported 7 years following the index surgery with an uncemented total hip arthroplasty and presented with osteolytic changes of the right proximal femur and later was lost to follow-up due to the COVID-19 pandemic. The patient returned again 2 years later presenting with the pseudotumor. Owing to the presence of extensive osteolysis with gross necrotic muscle mass around the proximal one-third of femur and since bone stock was available, reconstruction of the hip joint was not considered and hence a right side hind-quarter amputation was performed. Conclusion: This immune reaction was possibly exacerbated due to the underlying ankylosing spondylitis and chronic kidney disease requires more stringent follow up protocols and early intervention. It is, thereby, necessary to evaluate patients with serial radiography following total hip replacement, especially those with conditions which could accelerate the immune responses to the metal. This could potentially avoid an amputation and allow for reconstruction of the hip with appropriate immunomodulation.

Kaempferol attenuates particle-induced osteogenic impairment by regulating ER stress via the IRE1α-XBP1s pathway.

Periprosthetic osteolysis and subsequent aseptic loosening are the primary causes of failure following total joint arthroplasty. Wear particle-induced osteogenic impairment is recognized as an important contributing factor in the development of osteolysis, with endoplasmic reticulum (ER) stress emerging as a pivotal underlying mechanism. Hence, searching for potential therapeutic targets and agents capable of modulating ER stress in osteoblasts is crucial for preventing aseptic loosening. Kaempferol (KAE), a natural flavonol compound, has shown promising osteoprotective effects and anti-ER stress properties in diverse diseases. However, the influence of KAE on ER stress-mediated osteogenic impairment induced by wear particles remains unclear. In this study, we observed that KAE effectively relieved TiAl6V4 particles-induced osteolysis by improving osteogenesis in a mouse calvarial model. Furthermore, we demonstrated that KAE could attenuate ER stress-mediated apoptosis in osteoblasts exposed to TiAl6V4 particles, both in vitro and in vivo. Mechanistically, our results revealed that KAE mitigated ER stress-mediated apoptosis by upregulating the IRE1α-XBP1s pathway while concurrently partially inhibiting the IRE1α-regulated RIDD and JNK activation. Collectively, our findings suggest that KAE is a prospective therapeutic agent for treating wear particle-induced osteolysis and highlight the IRE1α-XBP1s pathway as a potential therapeutic target for preventing aseptic loosening.

Deletion of FNDC5/irisin modifies murine osteocyte function in a sex-specific manner.

Irisin, released from exercised muscle, has been shown to have beneficial effects on numerous tissues but its effects on bone are unclear. We found significant sex and genotype differences in bone from wildtype (WT) mice compared to mice lacking Fndc5 (knockout [KO]), with and without calcium deficiency. Despite their bone being indistinguishable from WT females, KO female mice were partially protected from osteocytic osteolysis and osteoclastic bone resorption when allowed to lactate or when placed on a low-calcium diet. Male KO mice have more but weaker bone compared to WT males, and when challenged with a low-calcium diet lost more bone than WT males. To begin to understand responsible molecular mechanisms, osteocyte transcriptomics was performed. Osteocytes from WT females had greater expression of genes associated with osteocytic osteolysis and osteoclastic bone resorption compared to WT males which had greater expression of genes associated with steroid and fatty acid metabolism. Few differences were observed between female KO and WT osteocytes, but with a low-calcium diet, the KO females had lower expression of genes responsible for osteocytic osteolysis and osteoclastic resorption than the WT females. Male KO osteocytes had lower expression of genes associated with steroid and fatty acid metabolism, but higher expression of genes associated with bone resorption compared to male WT. In conclusion, irisin plays a critical role in the development of the male but not the female skeleton and protects male but not female bone from calcium deficiency. We propose irisin ensures the survival of offspring by targeting the osteocyte to provide calcium in lactating females, a novel function for this myokine.

A mechanobiological model of bone metastasis reveals that mechanical stimulation inhibits the pro-osteolytic effects of breast cancer cells.

Bone is highly susceptible to cancer metastasis, and both tumor and bone cells enable tumor invasion through a "vicious cycle" of biochemical signaling. Tumor metastasis into bone also alters biophysical cues to both tumor and bone cells, which are highly sensitive to their mechanical environment. However, the mechanobiological feedback between these cells that perpetuate this cycle has not been studied. Here, we develop highly advanced in vitro and computational models to provide an advanced understanding of how tumor growth is regulated by the synergistic influence of tumor-bone cell signaling and mechanobiological cues. In particular, we develop a multicellular healthy and metastatic bone model that can account for physiological mechanical signals within a custom bioreactor. These models successfully recapitulated mineralization, mechanobiological responses, osteolysis, and metastatic activity. Ultimately, we demonstrate that mechanical stimulus provided protective effects against tumor-induced osteolysis, confirming the importance of mechanobiological factors in bone metastasis development.

Effects of apical periodontitis treatment on hyperglycaemia in diabetes: A prospective cohort study.

AIM: This prospective cohort study was undertaken to evaluate the success rate of root canal treatment (RCT) in type 2 diabetes mellitus (T2DM) patients with targeted level and unachieved targeted level of glycaemic control as well as the impact of RCT on the glucose blood level in T2DM patients. METHODOLOGY: Patients needing RCT were divided into three groups: these without T2DM, that is, the control group (CG), those with targeted level of glycated haemoglobin HbA1c < 7% (TL A1c) and the third ones with unachieved targeted level (UTL A1c), that is, with HbA1c ≥ 7%. Before RCT, HbA1c and the periapical index (PAI) score were assessed, as well as 1 year later. RESULTS: Our results showed less favourable treatment results of RCT such as a reduction of radiographic lesions in T2DM patients, particularly in subjects with UTL A1c. The intergroup analysis of PAI score at the 12-month follow-up revealed a significant difference in TL A1C (p = .022) and CG (p = .001) with respect to UTL A1c. Total number of healed teeth (PAI≤2) at the 12-month after RCT in UTL A1c was significantly lower in comparison to CG (p = .008). Contrariwise, RCT may improve the glycaemic control in diabetic patients with UTL A1c after 12 months of posttreatment. Regression analysis showed that UTL A1c patients were more likely to have AP persistence after endodontic treatment (OR = 4.788; CI: 1.157-19.816; p = .031). CONCLUSIONS: T2DM retards the AP healing and conversely AP contributes to increasing the inflammatory burden in T2DM. RCT reduces the cumulative inflammatory burden in T2DM and thus may contribute to improvement of glycaemic control particularly in patients with UTL A1c.