Pan-histone deacetylase inhibitor vorinostat suppresses osteoclastic bone resorption through modulation of RANKL-evoked signaling and ameliorates ovariectomy-induced bone loss.

BACKGROUND: Estrogen deficiency-mediated hyperactive osteoclast represents the leading role during the onset of postmenopausal osteoporosis. The activation of a series of signaling cascades triggered by RANKL-RANK interaction is crucial mechanism underlying osteoclastogenesis. Vorinostat (SAHA) is a broad-spectrum pan-histone deacetylase inhibitor (HDACi) and its effect on osteoporosis remains elusive. METHODS: The effects of SAHA on osteoclast maturation and bone resorptive activity were evaluated using in vitro osteoclastogenesis assay. To investigate the effect of SAHA on the osteoclast gene networks during osteoclast differentiation, we performed high-throughput transcriptome sequencing. Molecular docking and the assessment of RANKL-induced signaling cascades were conducted to confirm the underlying regulatory mechanism of SAHA on the action of RANKL-activated osteoclasts. Finally, we took advantage of a mouse model of estrogen-deficient osteoporosis to explore the clinical potential of SAHA. RESULTS: We showed here that SAHA suppressed RANKL-induced osteoclast differentiation concentration-dependently and disrupted osteoclastic bone resorption in vitro. Mechanistically, SAHA specifically bound to the predicted binding site of RANKL and blunt the interaction between RANKL and RANK. Then, by interfering with downstream NF-κB and MAPK signaling pathway activation, SAHA negatively regulated the activity of NFATc1, thus resulting in a significant reduction of osteoclast-specific gene transcripts and functional osteoclast-related protein expression. Moreover, we found a significant anti-osteoporotic role of SAHA in ovariectomized mice, which was probably realized through the inhibition of osteoclast formation and hyperactivation. CONCLUSION: These data reveal a high affinity between SAHA and RANKL, which results in blockade of RANKL-RANK interaction and thereby interferes with RANKL-induced signaling cascades and osteoclastic bone resorption, supporting a novel strategy for SAHA application as a promising therapeutic agent for osteoporosis.

Inhibition of MAGL attenuates Intervertebral Disc Degeneration by Delaying nucleus pulposus senescence through STING.

Intervertebral disc degeneration (IVDD) stands as the primary cause of low back pain (LBP). A significant contributor to IVDD is nucleus pulposus cell (NPC) senescence. However, the precise mechanisms underlying NPC senescence remain unclear. Monoacylglycerol lipase (MAGL) serves as the primary enzyme responsible for the hydrolysis of 2-arachidonoylglycerol (2-AG), breaking down monoglycerides into glycerol and fatty acids. It plays a crucial role in various pathological processes, including pain, inflammation, and oxidative stress. In this study, we utilized a lipopolysaccharide (LPS)-induced NPC senescence model and a rat acupuncture-induced IVDD model to investigate the role of MAGL in IVDD both in vitro and in vivo. Initially, our results showed that MAGL expression was increased 2.41-fold and 1.52-fold within NP tissues from IVDD patients and rats induced with acupuncture, respectively. This increase in MAGL expression was accompanied by elevated expression of p16INK4α. Following this, it was noted that the suppression of MAGL resulted in a notable decrease in the quantity of SA-ß-gal-positive cells and hindered the manifestation of p16INK4α and the inflammatory factor IL-1ß in NPCs. MAGL inhibition promotes type II collagen (Col-2) expression and inhibits matrix metalloproteinase 13 (MMP13), thereby restoring the balance of extracellular matrix (ECM) metabolism both in vitro and in vivo. A significant role for STING has also been demonstrated in the regulation of NPC senescence by MAGL. The expression of the STING protein was reduced by 57% upon the inhibition of MAGL. STING activation can replicate the effects of MAGL and substantially increase LPS-induced inflammation while accelerating the senescence of NPCs. These results strongly indicate that the inhibition of MAGL can significantly suppress nucleus pulposus senescence via its interaction with STING, consequently restoring the balance of ECM metabolism. This insight provides new perspectives for potential treatments for IVDD.

miR-145-5p regulates epithelial-mesenchymal-transition in nasal polyps through targeting Smad3.

Purpose: The prevalence of chronic rhinosinusitis ( CRS) is on the rise annually, and the absence of efficacious treatments imposes a substantial burden on both patients and society. The formation of nasal polyps in patients wi th CRS is cl osely related to tissue remodeling, and tissue remodeling is primarily influenced by epithelial mesenchymal transition (EMT). MicroRNA (miRNA) play s a pivotal role in the pathogenesis of numerous diseases through the miRNA mRNA regulatory network; however, the specific mechanism of miRNAs involved in the formation of nasal polyps is not clear. Methods: The expression of EMT markers and Smad3 were detected using western blot, quantitative real time polymerase chain reaction (qRT‒PCR), and immunohistochemistry, immunofluorescence staining. Differentially expressed genes in nasal polyps and normal tissues were screened through the gene expression omnibus (GEO) da tabase. To predict the target genes of miR 145 5p three different miRNA target prediction databases were used. The migratory ability of cells was verified by cell migration assay and wound h ealing assays. Results: miR 145 5p was linked with the process of EMT and significantly down regulation within the nasal polyp tissues. In vitro experiments, we found that miR 145 5p downregulation promoted EMT. The elevation in miR 145 5p levels reversed the EMT induce d by transforming growth factor ß1 ( TGF ß1). Bioinformatics found that miR 145 5p has a targeting relationship with Smad3. It is demonstrated that miR 145 5p exerts inhibitory Smad3 expression through further experiments. Conclusion: Overall, miR 145 5p emerges as a promising target to inhibit nasal polyp formation , and provide a theoretical basis for nanoparticle mediated miR 145 5p delivery for the treatment of nasal polyps.

Honeycomb-inspired ZIF-sealed interface enhances osseointegration via anti-infection and osteoimmunomodulation.

Implant-associated infections (IAIs) pose a significant threat to orthopedic surgeries. Bacteria colonizing the surface of implants disrupt bone formation-related cells and interfere with the osteoimmune system, resulting in an impaired immune microenvironment and osteogenesis disorders. Inspired by nature, a zeolitic imidazolate framework (ZIF)-sealed smart drug delivery system on Ti substrates (ZSTG) was developed for the "natural-artificial dual-enzyme intervention (NADEI)" strategy to address these challenges. The subtle sealing design of ZIF-8 on the TiO2 nanotubes ensured glucose oxidase (GOx) activity and prevented its premature leakage. In the acidic infection microenvironment, the degradation of ZIF-8 triggered the rapid release of GOx, which converted glucose into H2O2 for disinfection. The Zn2+ released from degraded ZIF-8, as a DNase mimic, can hydrolyze extracellular DNA, which further enhances H2O2-induced disinfection and prevents biofilm formation. Importantly, Zn2+-mediated M2 macrophage polarization significantly improved the impaired osteoimmune microenvironment, accelerating bone repair. Transcriptomics revealed that ZSTG effectively suppressed the inflammatory cascade induced by lipopolysaccharide while promoting cell proliferation, homeostasis maintenance, and bone repair. In vitro and in vivo results confirmed the superior anti-infective, osteoimmunomodulatory, and osteointegrative capacities of the ZSTG-mediated NADEI strategy. Overall, this smart bionic platform has significant potential for future clinical applications to treat IAIs.

Redox signaling and antioxidant defense in osteoclasts.

Bone remodeling is essential for the repair and replacement of damaged or aging bones. Continuous remodeling is necessary to prevent the accumulation of bone damage and to maintain bone strength and calcium balance. As bones age, the coupling mechanism between bone formation and absorption becomes dysregulated, and bone loss becomes dominant. Bone development and repair rely on interaction and communication between osteoclasts and surrounding cells. Osteoclasts are specialized cells that are accountable for bone resorption and degradation, and any abnormalities in their activity can result in notable alterations in bone structure and worsen disease symptoms. Recent findings from transgenic mouse models and bone analysis have greatly enhanced our understanding of the origin, differentiation pathway, and activation stages of osteoclasts. In this review, we explore osteoclasts and discuss the cellular and molecular events that drive their generation, focusing on intracellular oxidative and antioxidant signaling. This knowledge can help develop targeted therapies for diseases associated with osteoclast activation.

Restoration of constitutional alignment optimizes outcomes of computer navigated total knee arthroplasty: a prospective randomized controlled trial.

PURPOSE: The value of computer navigation in total knee arthroplasty (TKA) for arthritic knees continues to be debated. The purpose of this study was to evaluate the value of navigated TKA associated with updated alignment philosophy. METHODS: This prospective randomized controlled trial enrolled 38 consecutive patients (76 knees) and were randomly assigned to both groups. The demographic data and perioperative data were recorded. The coronal plane alignment of the knee (CPAK) classification was used to classify knee alignment phenotypes. Radiographic outcomes were measured and subgroup analysis was further performed. Clinical outcomes were evaluated using patient-reported outcome measures (PROMs). Surgery-related complications were recorded. RESULTS: The distribution of CPAK phenotypes following constitutional aligned TKA was equivalent to the native cohort, whereas the mechanical aligned TKA dramatically altered the phenotype distribution from type I and type II to type V and type IV. Final implant positioning was different between groups, with constitutional aligned TKA having larger cTCA (P = .004), joint line obliquity (P = .006), joint line distance (P = .033) and smaller sFCA (P = .013). Subgroup analysis showed higher actual accuracy of component positioning was achieved in navigated TKA, especially in knees with deformity of > 10° (P < .05). Patients reported higher HSS score at three months postoperatively in constitutional aligned group (P = .002). One patient in navigated group suffered femoral pin site fracture caused by a minor trauma. CONCLUSION: Computer navigated TKA allows for restoration of constitutional alignment and minimizes soft tissue release, which when compared to mechanical alignment may be associated with superior early outcomes.

Byakangelicol suppresses TiPs-stimulated osteoclastogenesis and bone destruction via COX-2/NF-κB signaling pathway.

Aseptic loosening (AL) is considered a significant cause of prosthesis revision after arthroplasty and a crucial factor in the longevity of an artificial joint prosthesis. The development of AL is primarily attributed to a series of biological reactions, such as peri-prosthetic osteolysis (PPO) induced by wear particles around the prosthesis. Chronic inflammation of the peri-prosthetic border tissue and hyperactivation of osteoclasts are key factors in this process, which are induced by metallic wear particles like Ti particles (TiPs). In our in vitro study, we observed that TiPs significantly enhanced the expression of inflammation-related genes, including COX-2, IL-1ß and IL-6. Through screening a traditional Chinese medicine database, we identified byakangelicol, a traditional Chinese medicine molecule that targets COX-2. Our results demonstrated that byakangelicol effectively inhibited TiPs-stimulated osteoclast activation. Mechanistically, we found that byakangelicol suppressed the expression of COX-2 and related pro-inflammatory factors by modulating macrophage polarization status and NF-κB signaling pathway. The in vivo results also demonstrated that byakangelicol effectively inhibited the expression of inflammation-related factors, thereby significantly alleviating TiPs-induced cranial osteolysis. These findings suggested that byakangelicol could potentially be a promising therapeutic approach for preventing PPO.

ADAM8 silencing suppresses the migration and invasion of fibroblast-like synoviocytes via FSCN1/MAPK cascade in osteoarthritis.

OBJECTIVE: Osteoarthritis (OA) is a degenerative joint disease that affects elderly populations worldwide, causing pain and disability. Alteration of the fibroblast-like synoviocytes (FLSs) phenotype leads to an imbalance in the synovial inflammatory microenvironment, which accelerates the progression of OA. Despite this knowledge, the specific molecular mechanisms of the synovium that affect OA are still unclear. METHODS: Both in vitro and in vivo experiments were undertaken to explore the role of ADAM8 playing in the synovial inflammatory of OA. A small interfering RNA (siRNA) was targeting ADAM8 to intervene. High-throughput sequencing was also used. RESULTS: Our sequencing analysis revealed significant upregulation of the MAPK signaling cascade and ADAM8 gene expression in IL-1ß-induced FLSs. The in vitro results demonstrated that ADAM8 blockade inhibited the invasion and migration of IL-1ß-induced FLSs, while also suppressing the expression of related matrix metallomatrix proteinases (MMPs). Furthermore, our study revealed that inhibiting ADAM8 weakened the inflammatory protein secretion and MAPK signaling networks in FLSs. Mechanically, it revealed that inhibiting ADAM8 had a significant effect on the expression of migration-related signaling proteins, specifically FSCN1. When siADAM8 was combined with BDP-13176, a FSCN1 inhibitor, the migration and invasion of FLSs was further inhibited. These results suggest that FSCN1 is a crucial downstream factor of ADAM8 in regulating the biological phenotypes of FLSs. The in vivo experiments demonstrated that ADAM8 inhibition effectively reduced synoviocytes inflammation and alleviated the progression of OA in rats. CONCLUSIONS: ADAM8 could be a promising therapeutic target for treating OA by targeting synovial inflammation.

Crosstalk Between the Neuroendocrine System and Bone Homeostasis.

The homeostasis of bone microenvironment is the foundation of bone health and comprises 2 concerted events: bone formation by osteoblasts and bone resorption by osteoclasts. In the early 21st century, leptin, an adipocytes-derived hormone, was found to affect bone homeostasis through hypothalamic relay and the sympathetic nervous system, involving neurotransmitters like serotonin and norepinephrine. This discovery has provided a new perspective regarding the synergistic effects of endocrine and nervous systems on skeletal homeostasis. Since then, more studies have been conducted, gradually uncovering the complex neuroendocrine regulation underlying bone homeostasis. Intriguingly, bone is also considered as an endocrine organ that can produce regulatory factors that in turn exert effects on neuroendocrine activities. After decades of exploration into bone regulation mechanisms, separate bioactive factors have been extensively investigated, whereas few studies have systematically shown a global view of bone homeostasis regulation. Therefore, we summarized the previously studied regulatory patterns from the nervous system and endocrine system to bone. This review will provide readers with a panoramic view of the intimate relationship between the neuroendocrine system and bone, compensating for the current understanding of the regulation patterns of bone homeostasis, and probably developing new therapeutic strategies for its related disorders.

What do osteoporosis and osteoarthritis have in common? An integrated study of overlapping differentially expressed genes in bone mesenchymal stem cells of osteoporosis and osteoarthritis.

OBJECTIVE: For identification of aberrantly expressed genes in mesenchymal stem cells of osteoporosis (OP) and osteoarthritis (OA), Gene Expression Omnibus (GEO) datasets were integrated to investigate the intersection point. METHODS: GSE35958 (osteoporosis) and GSE19664 (osteoarthritis) datasets were obtained from GEO database. The abnormally expressed genes were analyzed by GEO2R. Functional enrichment was explored by Metascape database and R software. The String database and Cytoscape software were used to build the protein-protein interaction network and identify hub genes. GSE35957 and GSE116925 were used as verification datasets. Single-cell analysis and pseudotime analysis were undertaken. CTDbase, Network Analyst, HPA database, HERB database and MIRW database were used to research the information, tissue and cell distribution, regulation, interaction and ingredients targeting the hub genes. Additionally, in vitro experiments such as RT-PCR, ALP staining and immunofluorescence were undertaken as verification tests. RESULTS: Ten hub genes were identified in this study. All these genes play an important role in bone or cartilage generation. They have diagnostic values and therapeutic potential for OA and OP. Single-cell analysis visualized the cell distribution and pseudotime distribution of these genes. Some potential therapeutic ingredients of these genes were identified, such as curcumin, wogonin and glycerin. In vitro experiments, RT-PCR results showed that COL9A3 and MMP3 were downregulated and PTH1R was upregulated during osteogenic induction of BMSC. Immunohistochemical results showed the expression trend of MMP3 and COL2A1. CONCLUSION: Ten abnormal hub genes of osteoporosis and osteoarthritis were identified successfully by this study. They were important regulatory genes for healthy bone and cartilage. These genes could be the common connections between osteoporosis and osteoarthritis as well as treatment targets. Further study of the regulatory mechanism and treatment effects of these genes would be valuable. The results of this study could contribute to further research.

CB2 regulates oxidative stress and osteoclastogenesis through NOX1-dependent signaling pathway in titanium particle-induced osteolysis.

Periprosthetic osteolysis (PPO) induced by wear particles at the interface between the prosthesis and bone is a crucial issue of periprosthetic bone loss and implant failure. After wear and tear, granular material accumulates around the joint prosthesis, causing a chronic inflammatory response, progressive osteoclast activation and eventual loosening of the prosthesis. Although many studies have been conducted to address bone loss after joint replacement surgeries, they have not fully addressed these issues. Focusing on osteoclast activation induced by particles has important theoretical implications. Cannabinoid type II receptor (CB2) is a seven-transmembrane receptor that is predominantly distributed in the human immune system and has been revealed to be highly expressed in bone-associated cells. Previous studies have shown that modulation of CB2 has a positive effect on bone metabolism. However, the exact mechanism has not yet been elucidated. In our experiments, we found that NOX1-mediated ROS accumulation was involved in titanium particle-stimulated osteoclast differentiation. Furthermore, we confirmed that CB2 blockade alleviated titanium particle-stimulated osteoclast activation by inhibiting the NOX1-mediated oxidative stress pathway. In animal experiments, downregulation of CB2 alleviated the occurrence of titanium particle-induced cranial osteolysis by inhibiting osteoclasts and scavenging intracellular ROS. Collectively, our results suggest that CB2 blockade may be an attractive and promising therapeutic scheme for particle-stimulated osteoclast differentiation and preventing PPO.

Spatiotemporal Immunomodulation and Biphasic Osteo-Vascular Aligned Electrospun Membrane for Diabetic Periosteum Regeneration.

Under diabetic conditions, blood glucose fluctuations and exacerbated immunopathological inflammatory environments pose significant challenges to periosteal regenerative repair strategies. Responsive immune regulation in damaged tissues is critical for the immune microenvironment, osteogenesis, and angiogenesis stabilization. Considering the high-glucose microenvironment of such acute injury sites, a functional glucose-responsive immunomodulation-assisted periosteal regeneration composite material-PLA（Polylactic Acid）/COLI(Collagen I）/Lipo(Liposome）-APY29 (PCLA)-is constructed. Aside from stimulating osteogenic differentiation, owing to the presence of surface self-assembled type I collagen in the scaffolds, PCLA can directly respond to focal area high-glucose microenvironments. The PCLA scaffolds trigger the release of APY29-loaded liposomes, shifting the macrophages toward the M2 phenotype, inhibiting the release of inflammatory cytokines, improving the bone immune microenvironment, and promoting osteogenic differentiation and angiogenesis. Bioinformatics analyses show that PCLA enhances bone repair by inhibiting the inflammatory signal pathway regulating the polarization direction and promoting osteogenic and angiogenic gene expression. In the calvarial periosteal defect model of diabetic rats, PCLA scaffolds induce M2 macrophage polarization and improve the inflammatory microenvironment, significantly accelerating periosteal repair. Overall, the PCLA scaffold material regulates immunity in fluctuating high-glucose inflammatory microenvironments, achieves relatively stable and favorable osteogenic microenvironments, and facilitates the effective design of functionalized biomaterials for bone regeneration therapy in patients with diabetes.

GLI1 facilitates collagen-induced arthritis in mice by collaborative regulation of DNA methyltransferases.

Rheumatoid arthritis (RA) is characterized by joint synovitis and bone destruction, the etiology of which remains to be explored. Many types of cells are involved in the progression of RA joint inflammation, among which the overactivation of M1 macrophages and osteoclasts has been thought to be an essential cause of joint inflammation and bone destruction. Glioma-associated oncogene homolog 1 (GLI1) has been revealed to be closely linked to bone metabolism. In this study, GLI1 expression in the synovial tissue of RA patients was positively correlated with RA-related scores and was highly expressed in collagen-induced arthritis (CIA) mouse articular macrophage-like cells. The decreased expression and inhibition of nuclear transfer of GLI1 downregulated macrophage M1 polarization and osteoclast activation, the effect of which was achieved by modulation of DNA methyltransferases (DNMTs) via transcriptional regulation and protein interactions. By pharmacological inhibition of GLI1, the proportion of proinflammatory macrophages and the number of osteoclasts were significantly reduced, and the joint inflammatory response and bone destruction in CIA mice were alleviated. This study clarified the mechanism of GLI1 in macrophage phenotypic changes and activation of osteoclasts, suggesting potential applications of GLI1 inhibitors in the clinical treatment of RA.

[Surgical technique of lateral unicompartmental knee arthroplasty and discussion of the maximum correction value in the treatment of knee valgus deformity].

Objective: To investigate the surgical technique and the short-term effectivenss of lateral unicompartmental knee arthroplasty (LUKA) through lateral approach in the treatment of valgus knee and to calculate the maximum value of the theoretical correction of knee valgus deformity. Methods: A retrospective analysis was performed on 16 patients (20 knees) who underwent LUKA and met the selection criteria between April 2021 and July 2022. There were 2 males and 14 females, aged 57-85 years (mean, 71.5 years). The disease duration ranged from 1 to 18 years, with an average of 11.9 years. Knee valgus was staged according to Ranawat classification, there were 6 knees of type Ⅰ, 13 knees of type Ⅱ, and 1 knee of type Ⅲ. All patients were assigned the expected correction value of genu valgus deformity by preoperative planning, including the correction value of lateral approach, intra-articular correction value, and residual knee valgus deformity value. The actual postoperative corrected values of the above indicators were recorded and the theoretical maximum correctable knee valgus deformity values were extrapolated. The operation time, intraoperative blood loss, incision length, hospital stay, hip-knee-ankle angle (HKA), mechanical lateral distal femoral angle (mLDFA), mechanical medial proximal tibia angle (mMPTA), joint line convergence angle (JLCA), posterior tibial slope (PTS), range of motion (ROM), Hospital for Special Surgery (HSS) score, and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score were also recorded for effectiveness evaluation. Results: The patients' incision length averaged 13.83 cm, operation time averaged 85.8 minutes, intraoperative blood loss averaged 74.9 mL, and hospital stay averaged 6.7 days. None of the patients suffered any significant intraoperative neurological or vascular injuries. All patients were followed up 10-27 months, with a mean of 17.9 months. One patient with bilateral knee valgus deformities had intra-articular infection in the left knee at 1 month after operation and the remaining patients had no complication such as prosthesis loosening, dislocation, and infection. The ROM, HSS score, and WOMAC score of knee joint significantly improved at each time point after operation when compared to those before operation, and the indicators further improved with time after operation, the differences were all significant ( P<0.05). Imaging measurement showed that HKA, mLDFA, JLCA, and PTS significantly improved at 3 days after operation ( P<0.05) except for mMPTA ( P>0.05). Postoperative evaluation of the knee valgus deformity correction values showed that the actual intra-articular correction values ranged from 0.54° to 10.97°, with a mean of 3.84°. The postoperative residual knee valgus deformity values ranged from 0.42° to 5.30°, with a mean of 3.59°. The actual correction values of lateral approach ranged from 0.21° to 12.73°, with a mean of 4.26°. Conclusion: LUKA through lateral approach for knee valgus deformity can achieve good early effectiveness. Preoperative planning can help surgeons rationally allocate the correction value of knee valgus deformity, provide corresponding treatment strategies, and the maximum theoretical correction value of knee valgus deformity can reach 25°.

Bio-orthogonal engineered peptide: A multi-functional strategy for the gene therapy of osteoporotic bone loss.

Osteoporosis is a degenerative disease affecting millions of elderly people globally and increases the risk of bone fractures due to the reduced bone density. Drugs are normally prescribed to treat osteoporosis, especially after surgical treatment of osteoporotic fractures. However, many anti-osteoporotic drugs produce deleterious side effects. The recent development of gene therapy utilizing oligonucleotides (ONs) has spurred the development of new therapies for osteoporosis. Nevertheless, most ONs lack the capability of cell penetration and lysosome escape and hence, intracellular delivery of ON remains a challenge. Herein, a novel strategy is demonstrated to efficiently deliver ON to cells by combining ON with the cell-penetrating peptide (CPP) via the bio-orthogonal click reaction. Several dopamine (DOPA) groups are also introduced into the fabricated peptide to scavenge intracellular reactive oxygen species (ROS). Owing to favorable properties such as good cytocompatibility, cell penetration, lysosome escape, ROS scavenging, and osteoclastogenesis suppression, the hybrid CPP-DOPA-ON peptide improves the osteoporotic conditions significantly in vivo even when bone implants are involved. This strategy has great potential in the treatment of osteoporosis and potentially broadens the scope of gene therapy.

The Emerging Role of the Mitochondrial Respiratory Chain in Skeletal Aging.

Maintenance of mitochondrial homeostasis is crucial for ensuring healthy mitochondria and normal cellular function. This process is primarily responsible for regulating processes that include mitochondrial OXPHOS, which generates ATP, as well as mitochondrial oxidative stress, apoptosis, calcium homeostasis, and mitophagy. Bone mesenchymal stem cells express factors that aid in bone formation and vascular growth. Positive regulation of hematopoietic stem cells in the bone marrow affects the differentiation of osteoclasts. Furthermore, the metabolic regulation of cells that play fundamental roles in various regions of the bone, as well as interactions within the bone microenvironment, actively participates in regulating bone integrity and aging. The maintenance of cellular homeostasis is dependent on the regulation of intracellular organelles, thus understanding the impact of mitochondrial functional changes on overall bone metabolism is crucially important. Recent studies have revealed that mitochondrial homeostasis can lead to morphological and functional abnormalities in senescent cells, particularly in the context of bone diseases. Mitochondrial dysfunction in skeletal diseases results in abnormal metabolism of bone-associated cells and a secondary dysregulated microenvironment within bone tissue. This imbalance in the oxidative system and immune disruption in the bone microenvironment ultimately leads to bone dysplasia. In this review, we examine the latest developments in mitochondrial respiratory chain regulation and its impacts on maintenance of bone health. Specifically, we explored whether enhancing mitochondrial function can reduce the occurrence of bone cell deterioration and improve bone metabolism. These findings offer prospects for developing bone remodeling biology strategies to treat age-related degenerative diseases.

REPIN1 regulates iron metabolism and osteoblast apoptosis in osteoporosis.

Osteoporosis is not well treated due to the difficulty of finding commonalities between the various types of it. Iron homeostasis is a vital component in supporting biochemical functions, and iron overload is recognized as a common risk factor for osteoporosis. In this research, we found that there is indeed evidence of iron accumulation in the bone tissue of patients with osteoporosis and REPIN1, as an origin specific DNA binding protein, may play a key role in this process. We revealed that sh-Repin1 therapy can rescue bone loss in an iron-overload-induced osteoporosis mouse model. Knockdown of Repin1 can inhibit apoptosis and enhance the resistance of osteoblasts to iron overload toxicity. REPIN1 promoted apoptosis by regulating iron metabolism in osteoblasts. Mechanistically, knockdown of Repin1 decreased the expression of Lcn2, which ameliorated the toxic effects of intracellular iron overload. The anti-iron effect of lentivirus sh-Repin1 was partially reversed or replicated by changing LCN2 expression level via si-RNA or plasmid, which indirectly verified the key regulatory role of LCN2 as a downstream target. Furthermore, the levels of BCL2 and BAX, which play a key role in the mitochondrial apoptosis pathway, were affected. In summary, based on the results of clinical specimens, animal models and in vitro experiments, for the first time, we proved the key role of REPIN1 in iron metabolism-related osteoporosis.

The role of ferroptosis in intervertebral disc degeneration.

Nucleus pulposus, annulus fibrosus, and cartilage endplate constitute an avascular intervertebral disc (IVD), which is crucial for spinal and intervertebral joint mobility. As one of the most widespread health issues worldwide, intervertebral disc degeneration (IVDD) is recognized as a key contributor to back and neck discomfort. A number of degenerative disorders have a strong correlation with ferroptosis, a recently identified novel regulated cell death (RCD) characterized by an iron-dependent mechanism and a buildup of lipid reactive oxygen species (ROS). There is growing interest in the part ferroptosis plays in IVDD pathophysiology. Inhibiting ferroptosis has been shown to control IVDD development. Several studies have demonstrated that in TBHP-induced oxidative stress models, changes in ferroptosis marker protein levels and increased lipid peroxidation lead to the degeneration of intervertebral disc cells, which subsequently aggravates IVDD. Similarly, IVDD is significantly relieved with the use of ferroptosis inhibitors. The purpose of this review was threefold: 1) to discuss the occurrence of ferroptosis in IVDD; 2) to understand the mechanism of ferroptosis and its role in IVDD pathophysiology; and 3) to investigate the feasibility and prospect of ferroptosis in IVDD treatment.

Osteocytes Exposed to Titanium Particles Inhibit Osteoblastic Cell Differentiation via Connexin 43.

Periprosthetic osteolysis (PPO) induced by wear particles is the most severe complication of total joint replacement; however, the mechanism behind PPO remains elusive. Previous studies have shown that osteocytes play important roles in wear-particle-induced osteolysis. In this study, we investigated the effects of connexin 43 (Cx43) on the regulation of osteocyte-to-osteoblast differentiation. We established an in vivo murine model of calvarial osteolysis induced by titanium (Ti) particles. The osteolysis characteristic and osteogenesis markers in the osteocyte-selective Cx43 (CKO)-deficient and wild-type (WT) mice were observed. The calvarial osteolysis induced by Ti particles was partially attenuated in CKO mice. The expression of ß-catenin and osteogenesis markers increased significantly in CKO mice. In vitro, the osteocytic cell line MLO-Y4 was treated with Ti particles. The co-culturing of MLO-Y4 cells with MC3T3-E1 osteoblastic cells was used to observe the effects of Ti-treated osteocytes on osteoblast differentiation. When Cx43 of MLO-Y4 cells was silenced or overexpressed, ß-catenin was detected. Additionally, co-immunoprecipitation detection of Cx43 and ß-catenin binding in MLO-Y4 cells and MC3T3-E1 cells was performed. Finally, ß-catenin expression in MC3T3-E1 cells and osteoblast differentiation were evaluated after 18α-glycyrrhetinic acid (18α-GA) was used to block the intercellular communication of Cx43 between MLO-Y4 and MC3T3-E1 cells. Ti particles increased Cx43 expression and decreased ß-catenin expression in MLO-Y4 cells. The silencing of Cx43 increased the ß-catenin expression, and the over-expression of Cx43 decreased the ß-catenin expression. In the co-culture model, Ti treatment of MLO-Y4 cells inhibited the osteoblastic differentiation of MC3T3-E1 cells and Cx43 silencing in MLO-Y4 cells attenuated the inhibitory effects on osteoblastic differentiation. With Cx43 silencing in the MLO-Y4 cells, the MC3T3-E1 cells, co-cultured alongside MLO-Y4, displayed decreased Cx43 expression, increased ß-catenin expression, activation of Runx2, and promotion of osteoblastic differentiation in vitro co-culture. Finally, Cx43 expression was found to be negatively correlated to the activity of the Wnt signaling pathway, mostly through the Cx43 binding of ß-catenin from its translocation to the nucleus. The results of our study suggest that Ti particles increased Cx43 expression in osteocytes and that osteocytes may participate in the regulation of osteoblast function via the Cx43 during PPO.