Application of a novel osteotomy instrumentation as a substitute tool in total hip arthroplasty.

BACKGROUND: Mechanical failure, power shortage, and inadvertent contamination of the oscillating saw occasionally occurs in actualizing femoral neck osteotomy during total hip arthroplasty (THA); however, no appropriate alternative solution is currently available. This study aimed to introduce a novel osteotomy instrumentation (fretsaw, jig, cable passer hook) as a substitute tool while the oscillating saw was unavailable during THA. METHODS: This study included 40 patients (40 hips) who underwent femoral neck osteotomy during primary THA using the new osteotomy instrumentation (n = 20) and the oscillating saw (n = 20). Clinical data and intraoperative findings of all patients were evaluated. RESULTS: The mean osteotomy time was 22.3 ± 3.1 s (range, 17-30 s) and 29.4 ± 3.7 s (range, 25-39 s) in the oscillating saw group and in the new osteotomy instrumentation group, respectively (P < 0.001). The Harris Hip Score (HHS) improved in both groups; the mean HSS was 82.3 ± 2.5 and 83.3 ± 3.5 in the oscillating saw group and new osteotomy instrumentation group at 6 months after surgery, respectively (P = 0.297). CONCLUSIONS: The original osteotomy instrumentation can be an ideal substitute tool for femoral neck osteotomy in THA, especially when the oscillating saw is unavailable or malfunctioning.

Positive Correlation Between the Femur Neck Shaft and Anteversion Angles: A Retrospective Computed Tomography Analysis in Patients With Developmental Dysplasia of the Hip.

BACKGROUND: This study aimed to explore the anatomical correlation between the femoral neck shaft angle (NSA) and femoral anteversion angle (AA) in patients with developmental dysplasia of the hip based on the Crowe classification and provide a novel method to estimate the femoral AA on anteroposterior pelvic radiographs. METHODS: A total of 208 patients with dysplastic hips who underwent total hip arthroplasty at our institution were retrospectively included. Preoperative physiological AA and NSA were determined via 3-dimensional computed tomography. Linear regressions and Pearson's coefficients were calculated to assess the correlation between the femoral NSA and femoral AA. RESULTS: A total of 416 hips were divided into 5 subgroups: 99 normal, 143 type I, 71 type II, 63 type III, and 40 type IV hips following the Crowe classification. Dysplastic femurs had significantly higher AAs than normal hips (25.2° vs 31.4° vs 33.3° vs 35.5° vs 41.7°). Significant positive correlations between the AA and NSA were observed in normal (r = 0.635), type I (r = 0.700), type II (r = 0.612), and type III (r = 0.638) hips (P < .001); however, no meaningful correlation was observed in type IV hips (r = 0.218, P = .176). CONCLUSION: The NSA and AA correlated positively and significantly in the normal and dysplastic Crowe type I-III hips. The relationship between the NSA and AA indicates torsion of the proximal femur and offers an opportunity for straightforward estimation of AA based on NSA.

Graphene-modified CePO4 nanorods effectively treat breast cancer-induced bone metastases and regulate macrophage polarization to improve osteo-inductive ability.

BACKGROUND: Breast cancer bone metastasis has become one of the most common complications; however, it may cause cancer recurrence and bone nonunion, as well as local bone defects. METHODS: Herein, In vitro, we verified the effect of bioscaffold materials on cell proliferation and apoptosis through a CCK8 trial, staining of live/dead cells, and flow cytometry. We used immunofluorescence technology and flow cytometry to verify whether bioscaffold materials regulate macrophage polarization, and we used ALP staining, alizarin red staining and PCR to verify whether bioscaffold material promotes bone regeneration. In vivo, we once again studied the effect of bioscaffold materials on tumors by measuring tumor volume in mice, Tunel staining, and caspase-3 immunofluorescence. We also constructed a mouse skull ultimate defect model to verify the effect on bone regeneration. RESULTS: Graphene oxide (GO) nanoparticles, hydrated CePO4 nanorods and bioactive chitosan (CS) are combined to form a bioactive multifunctional CePO4/CS/GO scaffold, with characteristics such as photothermal therapy to kill tumors, macrophage polarization to promote blood vessel formation, and induction of bone formation. CePO4/CS/GO scaffold activates the caspase-3 proteasein local tumor cells, thereby lysing the DNA between nucleosomes and causing apoptosis. On the one hand, the as-released Ce3+ ions promote M2 polarization of macrophages, which secretes vascular endothelial growth factor (VEGF) and Arginase-1 (Arg-1), which promotes angiogenesis. On the other hand, the as-released Ce3+ ions also activated the BMP-2/Smad signaling pathway which facilitated bone tissue regeneration. CONCLUSION: The multifunctional CePO4/CS/GO scaffolds may become a promising platform for therapy of breast cancer bone metastases.

Quercetin inhibits macrophage polarization through the p-38α/ß signalling pathway and regulates OPG/RANKL balance in a mouse skull model.

Aseptic loosening caused by wear particles is a common complication after total hip arthroplasty. We investigated the effect of the quercetin on wear particle-mediated macrophage polarization, inflammatory response and osteolysis. In vitro, we verified that Ti particles promoted the differentiation of RAW264.7 cells into M1 macrophages through p-38α/ß signalling pathway by using flow cytometry, immunofluorescence assay and small interfering p-38α/ß RNA. We used enzyme-linked immunosorbent assays to confirm that the protein expression of M1 macrophages increased in the presence of Ti particles and that these pro-inflammatory factors further regulated the imbalance of OPG/RANKL and promoted the differentiation of osteoclasts. However, this could be suppressed, and the protein expression of M2 macrophages was increased by the presence of the quercetin. In vivo, we revealed similar results in the mouse skull by µ-CT, H&E staining, immunohistochemistry and immunofluorescence assay. We obtained samples from patients with osteolytic tissue. Immunofluorescence analysis indicated that most of the macrophages surrounding the wear particles were M1 macrophages and that pro-inflammatory factors were released. Titanium particle-mediated M1 macrophage polarization, which caused the release of pro-inflammatory factors through the p-38α/ß signalling pathway, regulated OPG/RANKL balance. Macrophage polarization is expected to become a new clinical drug therapeutic target.

Prediction of Postoperative Stem Anteversion in Crowe Type II/III Developmental Dysplasia of the Hip on Preoperative Two-Dimensional Computed Tomography.

BACKGROUND: Preoperative planning is fundamental for total hip arthroplasty. This study investigated the optimal femoral neck level for measuring femoral anteversion to predict postoperative stem anteversion in developmental dysplasia of the hip and determined the predictive role of average anteversion based on the sagittal 3-point fixation. METHODS: Sixty-two Crowe type II/III dysplastic hips that underwent total hip arthroplasty were retrospectively analyzed. Preoperative and postoperative anteversion was measured via 2-dimensional computed tomography. Anterior and posterior cortex anteversions were measured at 6 levels of the proximal femur. Femoral anteversion at each level was calculated. Average anterior (lesser trochanter) and posterior cortex anteversions (femoral neck) were calculated based on the sagittal 3-point fixation. RESULTS: From the lesser trochanter to head-neck junction, femoral anteversion decreased gradually from more to less than stem anteversion. For hips with femoral neck height ≥10 mm, femoral anteversion at the 10-mm level above the lesser trochanter proximal base showed no significant difference with stem anteversion, with a good correlation for the single-wedge and an excellent correlation for the double-wedge stem. Average anterior (lesser trochanter proximal base) and posterior cortex anteversions (femoral neck at 10 mm above the lesser trochanter proximal base) showed no significant difference from stem anteversion, with excellent correlations. CONCLUSION: For Crowe type II/III hips with femoral neck height ≥10 mm, the 10-mm level above the lesser trochanter proximal base is an optimal choice for measuring femoral anteversion to predict postoperative stem anteversion. The average of anterior cortex anteversion at the lesser trochanter and posterior cortex anteversion at the femoral neck has a predictive role.

Differentially expressed genes between systemic sclerosis and rheumatoid arthritis.

BACKGROUND: Evidence is accumulating to characterise the key differences between systemic sclerosis (SSc) and rheumatoid arthritis (RA), which are similar but distinct systemic autoimmune diseases. However, the differences at the genetic level are not yet clear. Therefore, the aim of the present study was to identify key differential genes between patients with SSc and RA. METHODS: The Gene Expression Omnibus database was used to identify differentially expressed genes (DEGs) between SSc and RA biopsies. The DEGs were then functionally annotated using Gene Ontology (GO) terms and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways with the Database for Annotation, Visualization and Integrated Discovery (DAVID) tools. A protein-protein interaction (PPI) network was constructed with Cytoscape software. The Molecular Complex Detection (MCODE) plugin was also used to evaluate the biological importance of the constructed gene modules. RESULTS: A total of 13,556 DEGs were identified between the five SSc patients and seven RA patients, including 13,465 up-regulated genes and 91 down-regulated genes. Interestingly, the most significantly enriched GO terms of up- and down-regulated genes were related to extracellular involvement and immune activity, respectively, and the top six highly enriched KEGG pathways were related to the same processes. In the PPI network, the top 10 hub nodes and top four modules harboured the most relevant genes contributing to the differences between SSc and RA, including key genes such as IL6, EGF, JUN, FGF2, BMP2, FOS, BMP4, LRRK2, CTNNB1, EP300, CD79, and CXCL13. CONCLUSIONS: These genes such as IL6, EGF, JUN, FGF2, BMP2, FOS, BMP4, LRRK2, CTNNB1, EP300, CD79, and CXCL13 can serve as new targets for focused research on the distinct molecular pathogenesis of SSc and RA. Furthermore, these genes could serve as potential biomarkers for differential diagnoses or therapeutic targets for treatment.

Pilose antler peptide potentiates osteoblast differentiation and inhibits osteoclastogenesis via manipulating the NF-κB pathway.

Bones are inflexible yet ever-changing metabolic organs, and bone homeostasis is maintained through two delicately regulated processes: bone construction and bone reabsorption. An imbalance in bone metabolism is linked to most orthopedic diseases, including osteoporosis and rheumatoid arthritis. Importantly, tumor necrosis factor-α (TNF-α) blocks osteoblast differentiation and stimulates osteoclast formation, resulting in delayed deposition of new bone and accelerated bone resorption, especially in rheumatoid arthritis patients with inflammatory conditions. Pilose antler peptide (PAP) isolated and purified from deer antlers has been shown to have beneficial effects on chronic inflammation. In the present study, we studied the impact of PAP on osteoblast differentiation and evaluated the regulatory mechanism, with particular emphasis on the effect of PAP on TNF-α-mediated NF-κB signaling. Mouse primary osteoblast cells were activated with bone morphogenetic protein-2 (BMP-2) for osteoblast differentiation. A significant stimulatory effect of PAP in osteoblastogenesis was observed using ALP activity and Alizarin Red S staining assays. Meanwhile, PAP significantly rescued TNF-α-induced impairment of osteoblast formation as well as mineralization. Furthermore, we found a similar trend upon analyzing osteoblast-specific gene expression. PAP significantly rescued TNF-α-mediated decrease in expression of osteoblast-specific genes. A molecular mechanism assay indicated that PAP significantly inhibited TNF-α-mediated stimulation of NF-κB signaling activity, as well as nuclear translocation of its subunit p65. Moreover, over-expression of p65 reversed the stimulatory effects of PAP on osteoblast differentiation. Furthermore, we also identified that PAP dose dependently inhibit osteoclastogenesis, and this effect might be achieved via suppressing NF-κB activity. In summary, this study shows that PAP promotes osteoblast differentiation and blocks TNF-α-mediated suppression of osteoblastogenesis in vitro via the NF-κB/p65 pathway, as well as inhibits osteoclastsogenesis in vitro. Therefore, PAP, a novel drug with both antiresorptive and osteoanabolic activity, shows therapeutic potential as an alternative treatment for osteolytic diseases, including rheumatoid arthritis and osteoporosis.

Three-Dimensional Host Bone Coverage in Total Hip Arthroplasty for Crowe Types II and III Developmental Dysplasia of the Hip.

BACKGROUND: Recommendations for minimum cup coverage based on anteroposterior radiographs are widely used as an intraoperative guide in total hip arthroplasty for patients with developmental dysplasia of the hip. The purpose of this study was to examine the validity of two-dimensional (2D) measurement of coverage with three-dimensional (3D) coverage and to identify parameters for determining the 3D coverage during surgery. METHODS: We developed a technique to accurately reproduce the intraoperative anatomic geometry of the dysplastic acetabulum and measure the 3D cup coverage postoperatively. With this technique, we retrospectively analyzed the difference and correlation between 2D and 3D measurements of native bone coverage in 35 patients (45 hips) with Crowe II or III DDH. Linear regression analysis was performed to examine the intraoperative parameters related to coverage. The mean follow-up period was 7.64 years (range, 6.1-9.5 years). RESULTS: There was a significant difference and a fair correlation between 2D and 3D measurements. The 2D measurement underestimated the 3D cup coverage by approximately 13%. An excellent linear relationship was noted between the 3D coverage/uncoverage and the height of the uncovered portion (R2 = 0.8440, P < .0001). There was no case of loosening or revision during the follow-up. CONCLUSION: Current minimum cup coverage recommendations based on 2D radiograph measurements should not be used as a direct intraoperative guide. The height of the uncovered portion is a useful parameter to determine the 3D coverage during surgery.

Salicortin inhibits osteoclast differentiation and bone resorption by down-regulating JNK and NF-κB/NFATc1 signaling pathways.

Receptor activator of nuclear factor (NF)-κB ligand (RANKL)-activated signaling is essential for osteoclast differentiation, activation, and survival. Salicortin is a phenolic glycoside that has been isolated from many plants such as Populus and Salix species, and has been shown to have anti-amnesic and anti-adipogenic effects. In this study, we investigated the effect of salicortin on RANKL-induced osteoclasts formation, bone resorption, and activation of osteoclast-related signaling pathways. Salicortin suppressed RANKL-induced osteoclastogenesis in bone marrow macrophage cultures in a dose-dependent manner, and inhibited osteoclastic bone resorption activity without any cytotoxicity. Salicortin inhibited RANKL-induced c-Jun N-terminal kinase and NF-κB activation, concomitant with retarded IκBα phosphorylation and inhibition of p65 nuclear translocation, leading to impaired transcription of nuclear factor of activated T cells c1 (NFATc1) and expression of osteoclastic-specific genes. Taken together, our findings demonstrate that salicortin inhibits NF-κB and NFATc1 activation, leading to attenuation of osteoclastogenesis and bone resorption. Thus, salicortin may be of interest in developments of treatment for osteoclast related diseases.

Subchondral bone changes and the impacts on joint pain and articular cartilage degeneration in osteoarthritis.

Subchondral bone has received increasing attention in both basic and clinical research on osteoarthritis (OA). Subchondral bone in OA presents abnormalities in structure, biochemical composition, biomechanics and cellular function. Overall, subchondral bone mainly shows bone resorption in early OA and bone formation in late OA. More and more evidence suggests that abnormalities in subchondral bone of OA promote joint pain generation and articular cartilage degeneration. Inhibition or amelioration of subchondral bone abnormalities can reduce joint pain and can delay cartilage degeneration; thus, subchondral bone-targeted treatment promises to be a new treatment approach for OA. The pathological changes and the role of subchondral bone in OA still require further investigation.

The use of customized cages in revision total hip arthroplasty for Paprosky type III acetabular bone defects.

PURPOSE: Revision total hip arthroplasty (THA) is challenging if severe periacetabular bone loss is present. Here we describe a method that uses a customised cage to reconstruct an acetabulum with a massive bone defect. METHODS: Designed with the aid of the rapid prototyping technique, a customised cage with a hook, crest and flange or braids was made, and then utilized to reconstruct severe compromised acetabulum in revision THA since 2001. Twenty-two patients (23 hips) were included in this study. The mean patient age at the time of surgery was 60.9 years (range, 38-80 years). Three hips had massive acetabular bone defects of Paprosky type IIIA and 20 of type IIIB. The Harris hip score was used to evaluate hip function. Radiographs were taken to evaluate loosening of the cage and resorption of allograft bone. RESULTS: The average follow up was 81.6 ± 24.9 months. The mean Harris hip score improved from 39.6 pre-operatively to 80.9 at the final follow-up. There were no instances of deep infection, severe venous thrombosis, and nerve palsy. One patient who had an intra-operative rupture of the superior acetabular artery was successfully treated using the haemostatic suturing technique. Two patients experienced dislocation at post-operative days four and six, respectively, and both were treated with closed reduction and skin traction for three weeks. CONCLUSIONS: The present study demonstrates that a customised cage may be a promising option for THA revision of severely compromised acetabula. Extended follow-up is necessary to evaluate the long-term performance of this approach.

Fabrication, characterization, and biocompatibility of ethyl cellulose/carbonated hydroxyapatite composite coatings on Ti6Al4V.

In order to improve the biocompatibility of metallic implants, bioactive components are often used as coatings so that a real bond with the surrounding bone tissue can be formed. We prepared ethyl cellulose/carbonated hydroxyapatite composite coatings (ECHCs) on Ti6Al4V substrates with carbonated hydroxyapatite coatings (CHACs) without ethyl cellulose as controls. The inorganic constituent on the CHACs and ECHCs is calcium-deficient carbonated hydroxyapatite with a flaky texture and a low degree of crystallinity. The flaky carbonated hydroxyapatite plates aggregate to form macropores with an aperture size of around 0.5-2.0 µm. The presence of ethyl cellulose provides superior morphology, contact angle, and biocompatibility characteristics. In comparison to CHACs, ECHCs exhibit a smoother, crack-free surface because the cracks are filled by ethyl cellulose. Moreover, the contact angle of ECHCs is 37.3°, greater than that of CHACs (13.0°). Surface biocompatibility was investigated by using human bone mesenchymal stem cells (hBMSCs). The attachment, spreadability, viability and proliferation of hBMSCs on ECHCs are superior to those on CHACs. Thus, the crack-free ECHCs have excellent biocompatibility and are appropriate for use as biological implants.

The fate of osteophytes in the superolateral region of the acetabulum after total hip arthroplasty.

Acetabular osteophytes are common during total hip arthroplasty (THA). However, the fate and role of superolateral osteophytes of the acetabulum after THA remain unclear. The present study reviewed a series of radiographic changes in the osteophytes on the superolateral region of the acetabulum in 35 hips. The mean follow-up period was 42.2months. The results revealed that the osteophytes that were not in contact with the superolateral edge of acetabular cup were gradually absorbed after THA. In contrast, the osteophytes that were in contact with the superolateral edge of the acetabular cup underwent remodeling, formed regular trabecula, were stress bearing, and eventually integrated with the acetabular cup and the original acetabular bone, and should play a role in stabilizing the acetabular cup.

Subtracting-adding strategy for necrotic lesion segmentation in osteonecrosis of the femoral head.

PURPOSE: Osteonecrosis of the femoral head (ONFH) is a severe bone disease that can progressively lead to hip dysfunction. Accurately segmenting the necrotic lesion helps in diagnosing and treating ONFH. This paper aims at enhancing deep learning models for necrosis segmentation. METHODS: Necrotic lesions of ONFH are confined to the femoral head. Considering this domain knowledge, we introduce a preprocessing procedure, termed the "subtracting-adding" strategy, which explicitly incorporates this domain knowledge into the downstream deep neural network input. This strategy first removes the voxels outside the predefined volume of interest to "subtract" irrelevant information, and then it concatenates the bone mask with raw data to "add" anatomical structure information. RESULTS: Each of the tested off-the-shelf networks performed better with the help of the "subtracting-adding" strategy. The dice similarity coefficients increased by 10.93%, 9.23%, 9.38% and 1.60% for FCN, HRNet, SegNet and UNet, respectively. The improvements in FCN and HRNet were statistically significant. CONCLUSIONS: The "subtracting-adding" strategy enhances the performance of general-purpose networks in necrotic lesion segmentation. This strategy is compatible with various semantic segmentation networks, alleviating the need to design task-specific models.

Automatic planning and geometric analysis of the drilling path in core decompression surgery for osteonecrosis of the femoral head.

BACKGROUND AND OBJECTIVE: Core decompression surgery is an effective treatment method for patients with pre-collapse osteonecrosis of the femoral head (ONFH). The treatment relies on accurately predrilling the wire into the necrotic lesion. However, the surgical planning of this drilling path remains unclear. This paper aims to develop a framework to automatically plan the drilling path and analyze its geometric parameters. METHODOLOGY: The proposed system consists of two stages. The first stage is to detect the key points. Besides the entry point and target point for the drilling path, the center of the femoral head (FH) and the boundary points of the necrotic lesion are also detected for the subsequent geometric analysis. In the second stage, the geometric parameters of the drilling path are analyzed, including the size of the necrotic lesion, the length from the entry point to the target point, the relative location between the FH center and the necrosis center, and the angular range of the drilling path in the anterior-posterior (AP) direction and superior-inferior (SI) direction. RESULTS: All of the drilling paths designed by the proposed system were considered successful, starting from the proximal subtrochanteric region, terminating at the center of the necrotic lesion, and remaining within the femoral neck. The relative coordinates of the centers of the femoral head and necrotic lesion were (-0.89,5.14,2.63) mm for the left femurs and (1.55,5.92,2.63) mm for the right femurs, on average. The angular range of the drilling path was 39.99±29.58 degrees in the SI direction and 46.18±40.73 degrees in the AP direction. CONCLUSION: This study develops a framework that allows for automatic planning and geometric analysis of the drilling path in core decompression surgery. The target point of the drilling path primarily resides in the lateral-anterior-superior region relative to the femoral head center. Surgeons and researchers can benefit from our unified framework while still maintaining the flexibility to adapt to variations in surgical cases.

A New Method to Predict Postoperative Stem Anteversion in Total Hip Arthroplasty for Developmental Dysplasia of the Hip.

BACKGROUND: Preoperative evaluation of femoral anteversion to predict postoperative stem anteversion aids the selection of an appropriate prosthesis and optimizes the combined anteversion in total hip arthroplasty (THA) for developmental dysplasia of the hip (DDH). The conventional prediction methods are based on the femoral anteversion measurement at the location of the femoral head and/or neck. However, varied differences between femoral anteversion and postoperative stem anteversion were demonstrated. This study investigated the predictive role of a new method based on the principle of sagittal three-point fixation. METHODS: From January 2017 to December 2018, a total of 133 DDH hips that underwent THA were retrospectively analyzed. There were 76 Crowe type I, 27 type II, and 30 type III hips. The single-wedge stem was used in 49 hips, and the double-wedge stem was used in 84 hips. Preoperative native femoral anteversion at the femoral head-neck junction, anterior cortex anteversion at 2 levels of the lesser trochanter, posterior cortex anteversion at 5 levels of the femoral neck, and postoperative stem anteversion were measured using two-dimensional computed tomography. Predictive anteversion by the new method was calculated as the average anteversion formed by the anterior cortex at the lesser trochanter and the posterior cortex at the femoral neck. RESULTS: For hips with different neck heights, different Crowe types, different stem types, or different femoral anteversions, native femoral anteversion showed widely varied differences and correlations with stem anteversion, with differences ranging from -1.27 ± 8.33° to -13.67 ± 9.47° and correlations ranging from 0.122 (p = 0.705, no correlation) to 0.813. Predictive anteversion formed by the anterior cortex at the lesser trochanter proximal base and posterior cortex 10 mm above the lesser trochanter proximal base showed no significant difference with stem anteversion, with less varied differences (0.92 ± 7.52°) and good to excellent correlations (r = 0.826). CONCLUSION: Adopting our new method, predictive anteversion, measured as the average anteversion of the anterior cortex at the lesser trochanter proximal base and posterior cortex 10 mm above the lesser trochanter proximal base, predicted postoperative stem anteversion more reliably than native femoral anteversion.

Strontium ranelate reduces cartilage degeneration and subchondral bone remodeling in rat osteoarthritis model.

AIM: To investigate whether strontium ranelate (SR), a new antiosteoporotic agent, could attenuate cartilage degeneration and subchondral bone remodeling in osteoarthritis (OA). METHODS: Medial meniscal tear (MMT) operation was performed in adult SD rats to induce OA. SR (625 or 1800 mg·kg(-1)·d(-1)) was administered via gavage for 3 or 6 weeks. After the animals were sacrificed, articular cartilage degeneration was evaluated using toluidine blue O staining, SOX9 immunohistochemistry and TUNEL assay. The changes in microarchitecture indices and tissue mineral density (TMD), chemical composition (mineral-to-collagen ratio), and intrinsic mechanical properties of the subchondral bones were measured using micro-CT scanning, confocal Raman microspectroscopy and nanoindentation testing, respectively. RESULTS: The high-dose SR significantly attenuated cartilage matrix and chondrocyte loss at 6 weeks, and decreased chondrocyte apoptosis, improved the expression of SOX9, a critical transcription factor responsible for the expression of anabolic genes type II collagen and aggrecan, at both 3 and 6 weeks. Meanwhile, the high-dose SR also significantly attenuated the subchondral bone remodeling at both 3 and 6 weeks, as shown by the improved microarchitecture indices, TMD, mineral-to-collagen ratio and intrinsic mechanical properties. In contrast, the low-dose SR did not significantly change all the detection indices of cartilage and bone at both 3 and 6 weeks. CONCLUSION: The high-dose SR treatment can reduce articular cartilage degeneration and subchondral bone remodeling in the rat MMT model of OA.

Calcineurin/NFAT pathway mediates wear particle-induced TNF-α release and osteoclastogenesis from mice bone marrow macrophages in vitro.

AIM: To investigate the roles of the calcineurin/nuclear factor of activated T cells (NFAT) pathway in regulation of wear particles-induced cytokine release and osteoclastogenesis from mouse bone marrow macrophages in vitro. METHODS: Osteoclasts were induced from mouse bone marrow macrophages (BMMs) in the presence of 100 ng/mL receptor activator of NF-κB ligand (RANKL). Acridine orange staining and MTT assay were used to detect the cell viability. Osteoclastogenesis was determined using TRAP staining and RT-PCR. Bone pit resorption assay was used to examine osteoclast phenotype. The expression and cellular localization of NFATc1 were examined using RT-PCR and immunofluorescent staining. The production of TNFα was analyzed with ELISA. RESULTS: Titanium (Ti) or polymethylmethacrylate (PMMA) particles (0.1 mg/mL) did not significantly change the viability of BMMs, but twice increased the differentiation of BMMs into mature osteoclasts, and markedly increased TNF-α production. The TNF-α level in the PMMA group was significantly higher than in the Ti group (96 h). The expression of NFATc1 was found in BMMs in the presence of the wear particles and RANKL. In bone pit resorption assay, the wear particles significantly increased the resorption area and total number of resorption pits in BMMs-seeded ivory slices. Addition of 11R-VIVIT peptide (a specific inhibitor of calcineurin-mediated NFAT activation, 2.0 µmol/L) did not significantly affect the viability of BMMs, but abolished almost all the wear particle-induced alterations in BMMs. Furthermore, VIVIT reduced TNF-α production much more efficiently in the PMMA group than in the Ti group (96 h). CONCLUSION: Calcineurin/NFAT pathway mediates wear particles-induced TNF-α release and osteoclastogenesis from BMMs. Blockade of this signaling pathway with VIVIT may provide a promising therapeutic modality for the treatment of periprosthetic osteolysis.

CCL3 in the bone marrow microenvironment causes bone loss and bone marrow adiposity in aged mice.

The central physiological role of the bone marrow renders bone marrow stromal cells (BMSCs) particularly sensitive to aging. With bone aging, BMSCs acquire a differentiation potential bias in favor of adipogenesis over osteogenesis, and the underlying molecular mechanisms remain unclear. Herein, we investigated the factors underlying age-related changes in the bone marrow and their roles in BMSCs' differentiation. Antibody array revealed that CC chemokine ligand 3 (CCL3) accumulation occurred in the serum of naturally aged mice along with bone aging phenotypes, including bone loss, bone marrow adiposity, and imbalanced BMSC differentiation. In vivo Ccl3 deletion could rescue these phenotypes in aged mice. CCL3 improved the adipogenic differentiation potential of BMSCs, with a positive feedback loop between CCL3 and C/EBPα. CCL3 activated C/EBPα expression via STAT3, while C/EBPα activated CCL3 expression through direct promoter binding, facilitated by DNA hypomethylation. Moreover, CCL3 inhibited BMSCs' osteogenic differentiation potential by blocking ß-catenin activity mediated by ERK-activated Dickkopf-related protein 1 upregulation. Blocking CCL3 in vivo via neutralizing antibodies ameliorated trabecular bone loss and bone marrow adiposity in aged mice. This study provides insights regarding age-related bone loss and bone marrow adiposity pathogenesis and lays a foundation for the identification of new targets for senile osteoporosis treatment.