Enhancing Endogenous Hyaluronic Acid in Osteoarthritic Joints with an Anti-Inflammatory Supramolecular Nanofiber Hydrogel Delivering HAS2 Lentivirus.

Osteoarthritis (OA) management remains challenging because of its intricate pathogenesis. Intra-articular injections of drugs, such as glucocorticoids and hyaluronic acid (HA), have certain limitations, including the risk of joint infection, pain, and swelling. Hydrogel-based therapeutic strategies have attracted considerable attention because of their enormous therapeutic potential. Herein, a supramolecular nanofiber hydrogel is developed using dexamethasone sodium phosphate (DexP) as a vector to deliver lentivirus-encoding hyaluronan synthase 2 (HAS2) (HAS2@DexP-Gel). During hydrogel degradation, HAS2 lentivirus and DexP molecules are slowly released. Intra-articular injection of HAS2@DexP-Gel promotes endogenous HA production and suppresses synovial inflammation. Additionally, HAS2@DexP-Gel reduces subchondral bone resorption in the anterior cruciate ligament transection-induced OA mice, attenuates cartilage degeneration, and delays OA progression. HAS2@DexP-Gel exhibited good biocompatibility both in vitro and in vivo. The therapeutic mechanisms of the HAS2@DexP-Gel are investigated using single-cell RNA sequencing. HAS2@DexP-Gel optimizes the microenvironment of the synovial tissue by modulating the proportion of synovial cell subpopulations and regulating the interactions between synovial fibroblasts and macrophages. The innovative nanofiber hydrogel, HAS2@DexP-Gel, effectively enhances endogenous HA production while reducing synovial inflammation. This comprehensive approach holds promise for improving joint function, alleviating pain, and slowing OA progression, thereby providing significant benefits to patients.

Abnormal subchondral trabecular bone remodeling in knee osteoarthritis under the influence of knee alignment.

OBJECTIVE: This study aimed to investigate the abnormal subchondral trabecular bone (STB) remodeling in knee osteoarthritis (OA) under the influence of knee alignment [hip-knee-ankle (HKA) angle]. DESIGN: Forty-one patients with knee OA underwent radiographic examination before total knee arthroplasty (TKA) for the measurement of HKA angle. Tibial plateau specimens obtained during TKA were used for histomorphometric analyses to assess STB remodeling and cartilage degradation. Tartrate-resistant acidic phosphatase (TRAP) staining was used to test osteoclast activity. Osterix, osteocalcin, and sclerostin expression in the STB were determined using immunohistochemistry. RESULTS: The interaction between HKA angle and side (medial vs lateral of tibial plateau) was the main significant influence factor for STB remodeling and microstructure. The STB with the deviation of the knee alignment was accompanied by obvious abnormal bone remodeling and microstructural sclerosis. Bone volume fraction (BV/TV) was the only significant influence factor for OARSI score, the larger the BV/TV of STB, the higher the OARSI score of cartilage. Moreover, the tibial plateau affected by alignment had more TRAP + osteoclasts, Osterix + osteoprogenitors, and osteocalcin + osteoblasts and fewer sclerostin + osteocytes. CONCLUSIONS: The variation of tibial plateau STB remodeling activity and microstructure was associated with HKA angle and cartilage degradation. Knee malalignment may cause abnormal STB remodeling and microstructural sclerosis, which may potentially affect load stress transmission from the cartilage to the STB, thus resulting in accelerated knee OA progression.

D-dimer for diagnosis of periprosthetic joint infection: A meta-analysis.

BACKGROUND: The D-dimer test is easily available to detect periprosthetic joint infection (PJI). This study aimed to estimate the diagnostic accuracy of the D-dimer test in PJI diagnosis and identify possible independent factors affecting the diagnostic value of this test. METHODS: MEDLINE and EMBASE databases identified literature until February 2020 that utilized the D-dimer test for PJI diagnosis. The pooled sensitivity, specificity, area under the curve (AUC), diagnostic odds ratio (DOR), positive likelihood ratio (PLR), and negative likelihood ratio (NLR) were calculated to evaluate the diagnostic accuracy of the D-dimer test. Meta-regression and subgroup analyses were performed to assess potential heterogeneity. RESULTS: The databases identified 243 records, and eight studies were included in the final analysis. The pooled sensitivity and specificity of the D-dimer test for PJI diagnosis were 0.78 (95% confidence interval [CI], 0.69-0.84) and 0.74 (95% CI, 0.85-0.99), respectively. The AUCs and DORs of the D-dimer test were 0.83 (95% CI, 0.79-0.86) and 10 (95% CI, 4-24), respectively. The PLR and NLR of the D-dimer test for PJI detection were 3.0 (95% CI, 1.9-4.8) and 0.30 (95% CI, 0.20-0.47), respectively. The results of the meta-regression and subgroup analyses indicated that studies that excluded patients with hypercoagulation disorder had higher sensitivity (0.85 vs 0.86) and specificity (0.83 vs 0.62). The sensitivity of the D-dimer test also improved in studies that excluded patients with inflammatory arthritis (0.81 vs 0.75). CONCLUSION: The D-dimer test is a practical method for PJI diagnosis, especially in patients without history of hypercoagulation disorder and inflammatory arthritis.

Association Between Knee Malalignment and Ankle Degeneration in Patients With End-Stage Knee Osteoarthritis.

BACKGROUND: The association between knee malalignment and ankle degeneration has not been well established. This study aimed at determining whether knee malalignment and compensatory ankle morphology to knee malalignment are associated with the development and progression of ankle osteoarthritis (OA) in patients with end-stage knee OA. METHODS: We retrospectively reviewed 96 patients (106 knees) who underwent total knee arthroplasty. The progression of ankle OA, knee alignment, and ankle morphology were evaluated based on digital radiographs. Alignment deformity of the lower extremity was evaluated with hip-knee-ankle angle and medial proximal tibial angle (MPTA). Ankle morphology was evaluated by the lateral distal tibial angle, talar tilt, tibial plafond inclination angle, and ankle joint line orientation angle. RESULTS: The incidence of radiological ankle OA was observed in 39 of 106 cases. The MPTA (odds ratio = 0.72, P = .0009) and hip-knee-ankle angle (odds ratio = 1.13, P = .0169) were significantly associated with ankle OA. Among patients with tibial varus deformity, 26 of 49 had ankle OA. Among patients with neutral tibial alignment, 13 of 57 had radiological findings of ankle OA. MPTA was the only parameter associated with the progression of ankle OA. No association was observed between compensatory change in ankle morphology and the severity of ankle OA. CONCLUSION: Tibial varus deformity is associated with the development and progression of ankle OA; however, it is unclear whether it causes ankle OA. Due to the high incidence of ankle OA in total knee arthroplasty patients, it is reasonable to consider routine evaluation of the ankle.

Senescence of endplate osteoclasts induces sensory innervation and spinal pain.

Spinal pain affects individuals of all ages and is the most common musculoskeletal problem globally. Its clinical management remains a challenge as the underlying mechanisms leading to it are still unclear. Here, we report that significantly increased numbers of senescent osteoclasts (SnOCs) are observed in mouse models of spinal hypersensitivity, like lumbar spine instability (LSI) or aging, compared to controls. The larger population of SnOCs is associated with induced sensory nerve innervation, as well as the growth of H-type vessels, in the porous endplate. We show that deletion of senescent cells by administration of the senolytic drug Navitoclax (ABT263) results in significantly less spinal hypersensitivity, spinal degeneration, porosity of the endplate, sensory nerve innervation and H-type vessel growth in the endplate. We also show that there is significantly increased SnOC-mediated secretion of Netrin-1 and NGF, two well-established sensory nerve growth factors, compared to non-senescent OCs. These findings suggest that pharmacological elimination of SnOCs may be a potent therapy to treat spinal pain.

Senescence of endplate osteoclasts induces sensory innervation and spinal pain.

Spinal pain affects individuals of all ages and is the most common musculoskeletal problem globally. Its clinical management remains a challenge as the underlying mechanisms leading to it are still unclear. Here, we report that significantly increased numbers of senescent osteoclasts (SnOCs) are observed in mouse models of spinal hypersensitivity, like lumbar spine instability (LSI) or aging, compared to controls. The larger population of SnOCs is associated with induced sensory nerve innervation, as well as the growth of H-type vessels, in the porous endplate. We show that deletion of senescent cells by administration of the senolytic drug Navitoclax (ABT263) results in significantly less spinal hypersensitivity, spinal degeneration, porosity of the endplate, sensory nerve innervation, and H-type vessel growth in the endplate. We also show that there is significantly increased SnOC-mediated secretion of Netrin-1 and NGF, two well-established sensory nerve growth factors, compared to non-senescent OCs. These findings suggest that pharmacological elimination of SnOCs may be a potent therapy to treat spinal pain.

HKA Angle-A Reliable Planning Parameter for High Tibial Osteotomy: A Theoretical Analysis Using Standing Whole-Leg Radiographs.

High tibial osteotomy (HTO) is a recognized treatment for early-stage medial compartment knee osteoarthritis. Preoperative planning with standing whole-leg radiographs (WLRs) is essential for ensuring optimal postoperative alignment. The primary purpose of this study is to investigate the theoretical accuracy of the wedge opening required for two different preoperative planning parameters in open-wedge HTO. The second purpose is to theoretically determine which parameter is superior. Preoperative planning for HTO was performed with standing WLRs for 39 knees with isolated medial osteoarthritis. The Miniaci preoperative planning method was applied to correct the hip-knee-ankle (HKA) angle to 3to 6 degrees of valgus and the weight-bearing line (WBL) percentage within 60 to 70% of the width of the tibial plateau. To ensure that the HKA angle was between 3 and 6 degrees of valgus, the required accuracy window for the Miniaci angle was 3.25 ± 0.03 degrees (range, 3.20-3.30°). To ensure that the WBL percentage was between 60 and 70%, the accuracy window required for the Miniaci angle was 2.35 ± 0.13 degrees (range, 2.10-2.65°). This study suggests that to correct the HKA angle and the WBL percentage within the target range on two-dimensional WLRs, the Miniaci angle must be controlled to an accuracy of ± 1.63 and ± 1.18 degrees, respectively. Theoretically, the HKA angle is highly suitable as a preoperative planning parameter for HTO with a large permissible error and a small variability in the degree of change in the Miniaci angle (ΔMiniaci).

Irisin promotes fracture healing by improving osteogenesis and angiogenesis.

Background: Osteogenesis and angiogenesis are important for bone fracture healing. Irisin is a muscle-derived monokine that is associated with bone formation. Methods: To demonstrate the effect of irisin on bone fracture healing, closed mid-diaphyseal femur fractures were produced in 8-week-old C57BL/6 mice. Irisin was administrated intraperitoneally every other day after surgery, fracture healing was assessed by using X-rays. Bone morphometry of the fracture callus were assessed by using micro-computed tomography. Femurs of mice from each group were assessed by the three-point bending testing. Effect of irisin on osteogenic differentiation in mesenchymal stem cells in vitro was evaluated by quantitative real-time polymerase chain reaction (qRT-PCR), alkaline phosphatase staining and alizarin red staining. Angiogenesis of human umbilical vein endothelial cells (HUVECs) were evaluated by qRT-PCR, migration tests, and tube formation assays. Results: Increased callus formation, mineralization and tougher fracture healing were observed in the irisin-treated group than in the control group, indicating the better fracture callus healing due to Irisin treatment. The vessel surface and vessel volume fraction of the callus also increased in the irisin-treated group. The expression of BMP2, CD31, and VEGF in callus were enhanced in the irisin-treated group. In mouse bone mesenchymal stem cells, irisin promoted ALP expression and mineralization, and increased the expression of osteogenic genes, including OSX, Runx2, OPG, ALP, OCN and BMP2. Irisin also promoted HUVEC migration and tube formation. Expression of angiogenic genes, including ANGPT1, ANGPT2, VEGFb, CD31, FGF2, and PDGFRB in HUVECs were increased by irisin. Conclusion: All the results indicate irisin can promote fracture healing through osteogenesis and angiogenesis. These findings help in the understanding of muscle-bone interactions during fracture healing. The Translational Potential of this Article: Irisin was one of the most important monokine secreted by skeletal muscle. Studies have found that irisin have anabolic effect one bone remodeling through affecting osteocyte and osteoblast. Based on our study, irisin could promote bone fracture healing by increasing bone mass and vascularization, which provide a potential usage of irisin to promote fracture healing and improve clinical outcomes.

Associations of osteoclastogenesis and nerve growth in subchondral bone marrow lesions with clinical symptoms in knee osteoarthritis.

BACKGROUND/OBJECTIVE: Subchondral bone marrow lesions (BMLs) are common magnetic resonance imaging (MRI) features in joints affected by osteoarthritis (OA), however, their clinical impacts and mechanisms remain controversial. Thus, we aimed to investigate subchondral BMLs in knee OA patients who underwent total knee arthroplasty (TKA), then evaluate the associations of osteoclastogenesis and nerve growth in subchondral BMLs with clinical symptoms. METHODS: Total 70 patients with primary symptomatic knee OA were involved, then separated into three groups based on MRI (without BMLs group, n â€‹= â€‹14; BMLs without cyst group, n â€‹= â€‹37; BMLs with cyst group, n â€‹= â€‹19). Volume of BMLs and cyst-like lesions was calculated via the OsiriX system. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire was used to assess clinical symptoms. Histology and immunohistochemistry were deployed to assess subchondral osteoclastogenesis and nerve distribution. Pearson's correlation coefficient was used to evaluate the associations between volume of BMLs and joint symptoms, and to assess the associations of osteoclastogenesis and nerve growth in subchondral BMLs with joint symptoms. RESULTS: In BMLs combined with cyst group, patients exhibited increased osteoclastogenesis and nerve distribution in subchondral bone, as shown by increased expression of tartrate resistant acid phosphatase (TRAP) and protein gene product 9.5 (PGP9.5). Volume of subchondral cyst-like component was associated with joint pain (p â€‹< â€‹0.05). Subchondral osteoclastogenesis and nerve distribution were positively associated with joint pain in BMLs with cyst group (p â€‹< â€‹0.05). CONCLUSION: The subchondral cyst-like lesion was an independent factor for inducing pain in OA patients; osteoclastogenesis and nerve growth in subchondral cyst-like lesions could account for this joint pain. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: Our results indicated that the increased osteoclastogenesis and nerve growth in subchondral cyst-like lesions could account for the pain of OA joints. These findings may provide valuable basis for the treatment of OA.

Subchondral Trabecular Microstructure and Articular Cartilage Damage Variations Between Osteoarthritis and Osteoporotic Osteoarthritis: A Cross-sectional Cohort Study.

Osteoporotic osteoarthritis (OP-OA) is a specific type of OA. In this study, we aimed to assess the subchondral plate and rod microstructural differences between OA and OP-OA patients by using an individual trabeculae segmentation (ITS) system and to analyze the relationships between subchondral microstructures and cartilage damage in OA and OP-OA patients. Overall, 31 femoral heads were included in this study, which included 11 samples with OA and 13 samples with OP-OA; the normal control (NC) group contained 7 healthy femoral heads. ITS was performed to segment the subchondral trabecular bone into plate and rod trabeculae based on microcomputed tomography (micro-CT) images. We compared the plate and rod trabeculae of the subchondral trabecular bone between OA and OP-OA patients. The Osteoarthritis Research Society International (OARSI) score was employed to evaluate cartilage damage based on histological observations. Pearson's correlation coefficient and linear regression analysis were applied to analyze the relationships between subchondral microstructures and articular cartilage damage. Results showed that several microstructural parameters, including bone volume fraction (BV/TV), plate bone volume fraction (pBV/TV), rod bone volume fraction (rBV/TV), plate trabecular number (pTb.N), rod trabecular number (rTb.N), junction density between rod and plate (R-P Junc.D), and junction density between plate and plate (P-P Junc.D), were significantly decreased in patients with OP-OA compared with those in patients with OA (p < 0.05). Histological observations indicated that cartilage damage was more serious in patients with OP-OA than that in patients with OA (p < 0.05). Moreover, BV/TV, pBV/TV, pTb.N, and pTb.Th were significantly related to the OARSI score in both OA and OP-OA patients. These results indicated that there were differences in the subchondral rod and plate trabeculae between OA and OP-OA patients. Subchondral decreased plate trabeculae (pBV/TV, pTb.N, and pTb.Th) might account for cartilage damage in the progression of OP-OA. This study provided new insights to research OA when it is combined with OP.