Anterior cruciate ligament remnant preservation attenuates apoptosis and enhances the regeneration of hamstring tendon graft.

AIMS: The effects of remnant preservation on the anterior cruciate ligament (ACL) and its relationship with the tendon graft remain unclear. We hypothesized that the co-culture of remnant cells and bone marrow stromal cells (BMSCs) decreases apoptosis and enhances the activity of the hamstring tendons and tenocytes, thus aiding ACL reconstruction. METHODS: The ACL remnant, bone marrow, and hamstring tendons were surgically harvested from rabbits. The apoptosis rate, cell proliferation, and expression of types I and III collagen, transforming growth factor-ß (TGF-ß), vascular endothelial growth factor (VEGF), and tenogenic genes (scleraxis (SCX), tenascin C (TNC), and tenomodulin (TNMD)) of the hamstring tendons were compared between the co-culture medium (ACL remnant cells (ACLRCs) and BMSCs co-culture) and control medium (BMSCs-only culture). We also evaluated the apoptosis, cell proliferation, migration, and gene expression of hamstring tenocytes with exposure to co-culture and control media. RESULTS: Compared to BMSCs-only culture medium, the co-culture medium showed substantially decreased early and late apoptosis rates, attenuation of intrinsic and extrinsic apoptotic pathways, and enhanced proliferation of the hamstring tendons and tenocytes. In addition, the expression of collagen synthesis, TGF-ß, VEGF, and tenogenic genes in the hamstring tendons and tenocytes significantly increased in the co-culture medium compared to that in the control medium. CONCLUSION: In the presence of ACLRCs and BMSCs, the hamstring tendons and tenocytes significantly attenuated apoptosis and enhanced the expression of collagen synthesis, TGF-ß, VEGF, and tenogenic genes. This in vitro study suggests that the ACLRCs mixed with BMSCs could aid regeneration of the hamstring tendon graft during ACL reconstruction.Cite this article: Bone Joint Res 2023;12(1):9-21.

The Role of Mitochondrial Metabolism, AMPK-SIRT Mediated Pathway, LncRNA and MicroRNA in Osteoarthritis.

Osteoarthritis (OA) is the most common joint disease characterized by degeneration of articular cartilage and causes severe joint pain, physical disability, and impaired quality of life. Recently, it was found that mitochondria not only act as a powerhouse of cells that provide energy for cellular metabolism, but are also involved in crucial pathways responsible for maintaining chondrocyte physiology. Therefore, a growing amount of evidence emphasizes that impairment of mitochondrial function is associated with OA pathogenesis; however, the exact mechanism is not well known. Moreover, the AMP-activated protein kinase (AMPK)-Sirtuin (SIRT) signaling pathway, long non-coding RNA (lncRNA), and microRNA (miRNA) are important for regulating the physiological and pathological processes of chondrocytes, indicating that these may be targets for OA treatment. In this review, we first focus on the importance of mitochondria metabolic dysregulation related to OA. Then, we show recent evidence on the AMPK-SIRT mediated pathway associated with OA pathogenesis and potential treatment options. Finally, we discuss current research into the effects of lncRNA and miRNA on OA progression or inhibition.

Predicting the Poor Clinical and Radiographic Outcomes after the Anatomical Reduction and Internal Fixation of Posterior Wall Acetabular Fractures: A Retrospective Analysis.

Anatomical reduction is the fundamental principle of hip function restoration after posterior acetabular wall fractures (PWFs). Some patients exhibit poor outcomes despite anatomical reduction, and the prognostic factors leading to poor outcomes remain elusive. This study aimed to investigate the clinical and radiographic outcomes in patients with PWFs who had undergone anatomical reduction and internal fixation and to identify the predictors that impair clinical and radiologic outcomes. The clinical records of 60 patients with elementary PWFs who had undergone anatomical reduction and internal fixation between January 2005 and July 2015 were reviewed retrospectively. The Harris hip score (HHS) and modified Merle d'Aubigné clinical hip scores (MMAS) were used to evaluate the clinical outcome. Preoperative and final follow-up radiographs were cross checked to identify poor radiographic outcomes that included the presence of advanced osteoarthritis and osteonecrosis, as well as the need for conversion to total hip arthroplasty. Acetabular dome comminution was assessed from computerized tomography, and the outcomes were further evaluated according to the involvement of fragment comminution. The fracture comminution and age were negatively correlated with functional outcomes (correlation coefficients were -0.41 and -0.39 in HHS and MMAS, respectively) and were significantly related to the severity of osteoarthritis and osteonecrosis as well as the need for total hip arthroplasty. Regarding the radiographic factors, significantly worse post-operative HHS and MMAS were found in the fracture comminution group. In the subanalysis of the status of fracture comminution, patients with fragment comminution involving the acetabular dome had significantly lower functional scores than those with other fracture patterns. In conclusion, age, fracture comminution, and dome comminution were the prognostic indicators of advanced osteoarthritis and poor functional scores after the anatomical reduction and internal fixation of PWFs. We emphasized the relevance of acetabular dome comminution as an important contributing factor to clinical and radiographic outcomes.

Severe cellular stress drives apoptosis through a dual control mechanism independently of p53.

For past two decades, p53 has been claimed as the primary sensor initiating apoptosis. Under severe cellular stress, p53 transcriptional activity activates BH3-only proteins such as Bim, Puma, or Noxa to nullify the inhibitory effects of anti-apoptotic proteins on pro-apoptotic proteins for mitochondrial outer membrane permeabilization. Cellular stress determines the expression level of p53, and the amount of p53 corresponds to the magnitude of apoptosis. However, our studies indicated that Bim and Puma are not the target genes of p53 in three cancer models, prostate cancer, glioblastoma, and osteosarcoma. Bim counteracted with Bcl-xl to activate apoptosis independently of p53 in response to doxorubicin-induced severe DNA damage in prostate cancer. Moreover, the transcriptional activity of p53 was more related to cell cycle arrest other than apoptosis for responding to DNA damage stress generated by doxorubicin in prostate cancer and glioblastoma. A proteasome inhibitor that causes protein turnover dysfunction, bortezomib, produced apoptosis in a p53-independent manner in glioblastoma and osteosarcoma. p53 in terms of both protein level and nuclear localization in combining doxorubicin with bortezomib treatment was obviously lower than when using DOX alone, inversely correlated with the magnitude of apoptosis in glioblastoma. Using a BH3-mimetic, ABT-263, to treat doxorubicin-sensitive p53-wild type and doxorubicin-resistant p53-null osteosarcoma cells demonstrated only limited apoptotic response. The combination of doxorubicin or bortezomib with ABT-263 generated a synergistic outcome of apoptosis in both p53-wild type and p53-null osteosarcoma cells. Together, this suggested that p53 might have no role in doxorubicin-induced apoptosis in prostate cancer, glioblastoma and osteosarcoma. The effects of ABT-263 in single and combination treatment of osteosarcoma or prostate cancer indicated a dual control to regulate apoptosis in response to severe cellular stress. Whether our findings only apply in these three types of cancers or extend to other cancer types remains to be explored.

The Effects of a Patient-Specific Integrated Education Program on Pain, Perioperative Anxiety, and Functional Recovery following Total Knee Replacement.

The perioperative care of patients undergoing total knee arthroplasty (TKA) affects functional recovery and clinical outcomes. This study aims to introduce a patient-specific integrated education program (IEP) into the TKA clinical pathway and to evaluate patient outcomes between the intervention and control groups. We performed a two-site, two-arm, parallel-prospective controlled trial. The experiment group received an IEP incorporating verbal preoperative education, prehabilitation, multidisciplinary personalized rehabilitation during hospitalization, and supervised self-executed home-based exercise after discharge. The control group received regular TKA clinical care. We monitored the pain intensity, anxiety scores, and functional scores at six time points from the pre-operation interview to 3 months post-operation. The pain score was significantly decreased in the IEP group during hospitalization (p < 0.01) and before discharge (p < 0.05). The anxiety status was also improved after intervention in terms of state and trait anxiety inventory scores (p < 0.001) during hospitalization. The patient-reported (WOMAC) or physician-reported (American Knee Society Score) functional scores (p < 0.01 at most of the time points) all improved significantly under hospitalization. We found that the patient-specific IEP combining preoperative education, prehabilitation, the in-hospital group education class, and postoperative care navigation is effective in reducing postoperative pain, decreasing perioperative anxiety, and facilitating functional recovery following TKA.

Compound cellular stress maximizes apoptosis independently of p53 in glioblastoma.

We examined the apoptotic response of two glioblastoma cells, p53 wild type U87 and p53 mutated T98G, to doxorubicin, bortezomib, and vorinostat, which respectively target DNA, 26S proteasome and histone deacetylase, to clarify p53's function in apoptosis. We demonstrated that doxorubicin induced apoptosis in U87 cells but not in T98G cells. The level of p53 was definitively correlated to the extent of DNA damage and apoptosis initiation. Dominant-negative p53 reduced p21 expression, but did not affect doxorubicin-induced apoptosis, so the transcriptional activity of p53 seemed not to participate in doxorubicin-induced apoptosis. However, p53 concentrated into the nucleus during heavy apoptosis. Bortezomib could induce apoptosis in U87 with high sensitivity and T98G cells with low sensitivity. In contrast, vorinostat promoted apoptosis in both U87 and T98G cells and reduced the basal level of p53 in U87 cells, indicating that p53 played no role in the vorinostat-induced apoptosis. To clearly define the role of p53 in bortezomib- and doxorubicin-induced apoptosis, we combined doxorubicin with bortezomib to treat U87 cells to assess this combination's effect on apoptosis and p53 status. Interestingly, the combination of doxorubicin with bortezomib engendered compound stress, resulting in a synergistic outcome for apoptosis in U87 cells. However, the amounts of p53 in the total count and in the nucleus were much lower with the combination than with doxorubicin alone, suggesting that p53 played no role in either the compound stress, doxorubicin-only or bortezomib-induced apoptosis.

Impact of Wedge Effect on Outcomes of Intertrochanteric Fractures Treated with Intramedullary Proximal Femoral Nail.

The purpose of this study is to investigate the risk factors for wedge effect and its relevance between blade cut-out in patients with intertrochanteric fractures (ITF) treated with proximal femoral nail antirotation II (PFNA-II). A total of 113 patients with ITF treated with PFNA-II between 2012 and 2016 were retrospectively analyzed. Radiographic variables including preoperative fracture pattern, fracture classification, lateral wall fracture, and postoperative neck-shaft angle (NSA), femoral offset (FO), blade cut-out, and Parker's ratio were measured for analysis. An average of 4.16° of varus malalignment in NSA and 5.5 mm of femoral shaft lateralization in FO was found post-operatively. The presence of lateral wall fracture was significantly related to post-operative varus change of NSA (p < 0.05). After at least one year of follow up, the blade cut-out rate was 2.65% (3/113), and Parker's ratio was significantly higher in patients with blade cut-out (p = 0.0118). This study concluded that patients with ITF-present preoperative lateral wall fracture and postoperative higher Parker's ratio in AP radiography showed higher incidence of wedge effect that might increase risk of blade cut out.

Severe cellular stress activates apoptosis independently of p53 in osteosarcoma.

Apoptosis induced by doxorubicin, bortezomib, or paclitaxel, targeting DNA, 26S proteasome, and microtubules respectively, was assessed in two osteosarcoma cells, p53 wild-type U2OS and p53-null MG63 cells. Doxorubicin-induced apoptosis only occurred in U2OS, not in MG63. In contrast, bortezomib and paclitaxel could drive U2OS or MG63 toward apoptosis effectively, suggesting that apoptosis induced by bortezomib or paclitaxel is p53-independent. The expressions of Bcl2 family members such as Bcl2, Bcl-xl, and Puma could be seen in U2OS and MG63 cells with or without doxorubicin, bortezomib, or paclitaxel treatment. In contrast, another member, Bim, only could be observed in U2OS, not in MG63, under the same conditions. Bim knockdown did not affect the doxorubicin-induced apoptosis in U2OS, suggested that a BH3-only protein other than Bim might participate in apoptosis induced by doxorubicin. Using a BH3-mimetic, ABT-263, to inhibit Bcl2 or Bcl-xl produced a limited apoptotic response in U2OS and MG63 cells, suggesting that this BH3-mimetic cannot activate the Bax/Bak pathway efficiently. Significantly, ABT-263 enhanced doxorubicin- and bortezomib-induced apoptosis synergistically in U2OS and MG63 cells. These results implied that the severe cellular stress caused by doxorubicin or bortezomib might be mediated through a dual process to control apoptosis. Respectively, doxorubicin or bortezomib activates a BH3-only protein in one way and corresponding unknown factors in another way to affect mitochondrial outer membrane permeability, resulting in apoptosis. The combination of doxorubicin with ABT-263 could produce synergistic apoptosis in MG63 cells, which lack p53, suggesting that p53 has no role in doxorubicin-induced apoptosis in osteosarcoma. In addition, ABT-263 enhanced paclitaxel to induce moderate levels of apoptosis.

Molecular Weight of Hyaluronic Acid Has Major Influence on Its Efficacy and Safety for Viscosupplementation in Hip Osteoarthritis: A Systematic Review and Meta-Analysis.

BACKGROUND: This study aimed to compare the efficacy and safety of intra-articular hyaluronic acid (HA) injection with different molecular weights (MWs) for treating hip osteoarthritis (OA). METHODS: A systematic literature search for relevant studies was conducted in 3 electronic databases, including PubMed, BMJ Journals, and Cochrane Library, from inception to April 2020. Extracted outcomes included visual analogue scale (VAS) (1, 3, and 6 months), Lequesne index (3 and 6 months), and adverse effects. HAs were classified into low-molecular-weight (LMW), moderate-molecular-weight (MMW), high-molecular-weight (HMW), and ultra-high-molecular-weight (UHMW) groups. Meta-analysis was performed using Review Manager 5.3. RESULTS: A total of 15 studies with 614 patients were included. Our meta-analysis showed that the HMW HA group had the best improvement in VAS and Lequesne index compared with other HA groups for all the follow-up visits. Moreover, the HMW group demonstrated significantly better improvement than the other groups in VAS at 6-month follow-up and in Lequesne index at 3- and 6-month follow-ups. Analysis for adverse effects revealed low rates of systemic adverse effects (≤0.6%) in all groups and similar rate of local adverse effects (around 10%) among the groups except for UHMW HA group (37.5%). CONCLUSION: Among different MWs of HA for treating hip OA, HMW HA injection demonstrated the best efficacy for up to 6 months after treatment without increased risk of adverse effects. Further studies with more comprehensive data and a higher level of evidence are required to prove our results.

Application of microRNA in Human Osteoporosis and Fragility Fracture: A Systemic Review of Literatures.

MicroRNAs (miRNAs) could serve as ideal entry points to the deregulated pathways in osteoporosis due to their relatively simple upstream and downstream relationships with other molecules in the signaling cascades. Our study aimed to give a comprehensive review of the already identified miRNAs in osteoporosis from human blood samples and provide useful information for their clinical application. A systematic literature search for relevant studies was conducted in the Pubmed database from inception to December 2020. We set two essential inclusion criteria: human blood sampling and design of controlled studies. We sorted the results of analysis on human blood samples according to the study settings and compiled the most promising miRNAs with analyzed diagnostic values. Furthermore, in vitro and in vivo evidence for the mechanisms of the identified miRNAs was also illustrated. Based on both diagnostic value and evidence of mechanism from in vitro and in vivo experiments, miR-23b-3p, miR-140-3p, miR-300, miR-155-5p, miR-208a-3p, and miR-637 were preferred candidates in diagnostic panels and as therapeutic agents. Further studies are needed to build sound foundations for the clinical usage of miRNAs in osteoporosis.

The Potential of Calcium/Phosphate Containing MAO Implanted in Bone Tissue Regeneration and Biological Characteristics.

Micro arc oxidation (MAO) is a prominent surface treatment to form bioceramic coating layers with beneficial physical, chemical, and biological properties on the metal substrates for biomaterial applications. In this study, MAO treatment has been performed to modify the surface characteristics of AZ31 Mg alloy to enhance the biocompatibility and corrosion resistance for implant applications by using an electrolytic mixture of Ca3(PO4)2 and C10H16N2O8 (EDTA) in the solutions. For this purpose, the calcium phosphate (Ca-P) containing thin film was successfully fabricated on the surface of the implant material. After in-vivo implantation into the rabbit bone for four weeks, the apparent growth of soft tissues and bone healing effects have been documented. The morphology, microstructure, chemical composition, and phase structures of the coating were identified by SEM, XPS, and XRD. The corrosion resistance of the coating was analyzed by polarization and salt spray test. The coatings consist of Ca-P compounds continuously have proliferation activity and show better corrosion resistance and lower roughness in comparison to mere MAO coated AZ31. The corrosion current density decreased to approximately 2.81 × 10-7 A/cm2 and roughness was reduced to 0.622 µm. Thus, based on the results, it was anticipated that the development of degradable materials and implants would be feasible using this method. This study aims to fabricate MAO coatings for orthopedic magnesium implants that can enhance bioactivity, biocompatibility, and prevent additional surgery and implant-related infections to be used in clinical applications.

Effect of Freshly Isolated Bone Marrow Mononuclear Cells and Cultured Bone Marrow Stromal Cells in Graft Cell Repopulation and Tendon-Bone Healing after Allograft Anterior Cruciate Ligament Reconstruction.

Graft cell repopulation and tendon-bone tunnel healing are important after allograft anterior cruciate ligament reconstruction (ACLR). Freshly isolated bone marrow mononuclear cells (BMMNCs) have the advantage of short isolation time during surgery and may enhance tissue regeneration. Thus, we hypothesized that the effect of intra-articular BMMNCs in post-allograft ACLR treatment is comparable to that of cultured bone marrow stromal cells (BMSCs). A rabbit model of hamstring allograft ACLR was used in this study. Animals were randomly assigned to the BMMNC, BMSC, and control groups. Fresh BMMNCs isolated from the iliac crest during surgery and cultured BMSCs at passage four were used in this study. A total of 1 × 107 BMMNCs or BMSCs in 100 µL phosphate-buffered saline were injected into the knee joint immediately after ACLR. The control group was not injected with cells. At two and six weeks post operation, we assessed graft cell repopulation with histological and cell tracking staining (PKH26), and tendon-bone healing with histological micro-computed tomography and immunohistochemical analyses for collagen I and monocyte chemoattractant protein-1 (MCP1). At two weeks post operation, there was no significant difference in the total cell population within the allograft among the three groups. However, the control group showed significantly higher cell population within the allograft than that of BM cell groups at six weeks. Histological examination of proximal tibia revealed that the intra-articular delivered cells infiltrated into the tendon-bone interface. Compared to the control group, the BM cell groups showed broader gaps with interfacial fibrocartilage healing, similar collagen I level, and higher MCP1 expression in the early stage. Micro-CT did not reveal any significant difference among the three groups. BMMNCs and BMSCs had comparable effects on cell repopulation and interfacial allograft-bone healing. Intra-articular BM cells delivery had limited benefits on graft cell repopulation and caused higher inflammation than that in the control group in the early stage, with fibrocartilage formation in the tendon-bone interface after allograft ACLR.

An Intermediate Concentration of Calcium with Antioxidant Supplement in Culture Medium Enhances Proliferation and Decreases the Aging of Bone Marrow Mesenchymal Stem Cells.

Human bone marrow stem cells (HBMSCs) are isolated from the bone marrow. Stem cells can self-renew and differentiate into various types of cells. They are able to regenerate kinds of tissue that are potentially used for tissue engineering. To maintain and expand these cells under culture conditions is difficult-they are easily triggered for differentiation or death. In this study, we describe a new culture formula to culture isolated HBMSCs. This new formula was modified from NCDB 153, a medium with low calcium, supplied with 5% FBS, extra growth factor added to it, and supplemented with N-acetyl-L-cysteine and L-ascorbic acid-2-phosphate to maintain the cells in a steady stage. The cells retain these characteristics as primarily isolated HBMSCs. Moreover, our new formula keeps HBMSCs with high proliferation rate and multiple linage differentiation ability, such as osteoblastogenesis, chondrogenesis, and adipogenesis. It also retains HBMSCs with stable chromosome, DNA, telomere length, and telomerase activity, even after long-term culture. Senescence can be minimized under this new formulation and carcinogenesis of stem cells can also be prevented. These modifications greatly enhance the survival rate, growth rate, and basal characteristics of isolated HBMSCs, which will be very helpful in stem cell research.

Intra-Articular Injection of (-)-Epigallocatechin 3-Gallate (EGCG) Ameliorates Cartilage Degeneration in Guinea Pigs with Spontaneous Osteoarthritis.

Osteoarthritis (OA) is the most prevalent joint disease that causes an enormous burden of disease worldwide. (-)-Epigallocatechin 3-gallate (EGCG) has been reported to reduce post-traumatic OA progression through its anti-inflammatory property. Aging is the most crucial risk factor of OA, and the majority of OA incidences are related to age and not trauma. In this study, we assess whether EGCG can ameliorate cartilage degradation in primary OA. In an in-vitro study, real-time PCR was performed to assess the expression of genes associated with human articular chondrocyte homeostasis. A spontaneously occurring OA model in guinea pigs was used to investigate the effect of EGCG in vivo. OA severity was evaluated using Safranin O staining and Osteoarthritis Research Society International (OARSI) scores, as well as by immunohistochemical (IHC) analysis to determine the protein level of type II collagen (Col II), matrix metalloproteinase 13 (MMP-13), and p16 ink4a in articular cartilage. In the in-vitro study, EGCG increased the gene expression of aggrecan and Col II and decreased the expression of interleukin-1, cyclooxygenase 2, MMP-13, alkaline phosphatase, Col X, and p16 Ink4a; EGCG treatment also attenuated the degraded cartilage with a lower OARSI score. Meanwhile, IHC results showed that EGCG exerted an anti-OA effect by reducing ECM degradation, cartilage inflammation, and cell senescence with a less-immunostained Col II, MMP-13, and p16 Ink4a. In conclusion, these findings suggest that EGCG may be a potential disease-modifying OA drug for the treatment of primary OA.

Intra-Articular Injection of (-)-Epigallocatechin 3-Gallate to Attenuate Articular Cartilage Degeneration by Enhancing Autophagy in a Post-Traumatic Osteoarthritis Rat Model.

(-)-Epigallocatechin 3-gallate (EGCG) is the main active green tea catechin and has a wide variety of benefits for health. Post-traumatic osteoarthritis (PTOA) occurs as a consequence of joint injuries that commonly happen in the young population. In this study, we investigated the effects of EGCG on PTOA prevention by using the anterior cruciate ligament transection (ACLT)-OA model and further investigated the roles of autophagy in OA treatment. Our results showed that intra-articular injection of EGCG significantly improved the functional performances and decreased cartilage degradation. EGCG treatment attenuated the inflammation on synovial tissue and cartilage through less immunostained cyclooxygenase-2 and matrix metalloproteinase-13. We further noted EGCG may modulate the chondrocyte apoptosis by activation of the cytoprotective autophagy through reducing the expression of the mTOR and enhancing the expression of microtubule-associated protein light chain 3, beclin-1, and p62. In conclusion, intra-articular injection of EGCG after ACL injury inhibited the joint inflammation and cartilage degradation, thereby increasing joint function. EGCG treatment also reduced the chondrocyte apoptosis, possibly by activating autophagy. These findings suggested that EGCG may be a potential disease-modifying drug for preventing OA progression.

Osteoprotective Roles of Green Tea Catechins.

Osteoporosis is the second most common disease only secondary to cardiovascular disease, with the risk of fracture increasing with age. Osteoporosis is caused by an imbalance between osteoblastogenesis and osteoclastogenesis processes. Osteoclastogenesis may be enhanced, osteoblastogenesis may be reduced, or both may be evident. Inflammation and high reactive oxygen enhance osteoclastogenesis while reducing osteoblastogenesis by inducing osteoblast apoptosis and suppressing osteoblastic proliferation and differentiation. Catechins, the main polyphenols found in green tea with potent anti-oxidant and anti-inflammatory properties, can counteract the deleterious effects of the imbalance of osteoblastogenesis and osteoclastogenesis caused by osteoporosis. Green tea catechins can attenuate osteoclastogenesis by enhancing apoptosis of osteoclasts, hampering osteoclastogenesis, and prohibiting bone resorption in vitro. Catechin effects can be directly exerted on pre-osteoclasts/osteoclasts or indirectly exerted via the modulation of mesenchymal stem cells (MSCs)/stromal cell regulation of pre-osteoclasts through activation of the nuclear factor kB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system. Catechins also can enhance osteoblastogenesis by enhancing osteogenic differentiation of MSCs and increasing osteoblastic survival, proliferation, differentiation, and mineralization. The in vitro effects of catechins on osteogenesis have been confirmed in several animal models, as well as in epidemiological observational studies on human subjects. Even though randomized control trials have not shown that catechins provide anti-fracture efficacy, safety data in the trials are promising. A large-scale, placebo-controlled, long-term randomized trial with a tea regimen intervention of optimal duration is required to determine anti-fracture efficacy.

Green Tea Catechin (-)-Epigallocatechin-3-Gallate (EGCG) Facilitates Fracture Healing.

Green tea drinking can ameliorate postmenopausal osteoporosis by increasing the bone mineral density. (-)-Epigallocatechin-3-gallate (EGCG), the abundant and active compound of tea catechin, was proven to be able to reduce bone loss and ameliorate microarchitecture in female ovariectomized rats. EGCG can also enhance the osteogenic differentiation of murine bone marrow mesenchymal stem cells and inhibit the osteoclastogenesis in RAW264.7 cells by modulation of the receptor activator of nuclear factor-kB (RANK)/RANK ligand (RANKL)/osteoprotegrin (OPG) (RANK/RANKL/OPG) pathway. Our previous study also found that EGCG can promote bone defect healing in the distal femur partially via bone morphogenetic protein-2 (BMP-2). Considering the osteoinduction property of BMP-2, we hypothesized that EGCG could accelerate the bone healing process with an increased expression of BMP-2. In this manuscript, we studied whether the local use of EGCG can facilitate tibial fracture healing. Fifty-six 4-month-old rats were randomly assigned to two groups after being weight-matched: a control group with vehicle treatment (Ctrl) and a study group with 10 µmol/L, 40 µL, EGCG treatment (EGCG). Two days after the operation, the rats were treated daily with EGCG or vehicle by percutaneous local injection for 2 weeks. The application of EGCG enhanced callus formation by increasing the bone volume and subsequently improved the mechanical properties of the tibial bone, including the maximal load, break load, stiffness, and Young's modulus. The results of the histology and BMP-2 immunohistochemistry staining showed that EGCG treatment accelerated the bone matrix formation and produced a stronger expression of BMP-2. Taken together, this study for the first time demonstrated that local treatment of EGCG can accelerate the fracture healing process at least partly via BMP-2.

Impact of orthogeriatric care, comorbidity, and complication on 1-year mortality in surgical hip fracture patients: An observational study.

After acute hip surgery, the 1-year mortality rate is high. Therefore, this study evaluated the risk factors for 1-year mortality. The purposes of this study was first to examine the effect of integrated care on 1-year mortality in surgical patients and secondly to explore magnitude of comorbidity and complication on mortality.This retrospective cohort study included 313 patients received surgery for hip fragility fracture. Patients with multiple fractures or combined trauma were excluded. The patients were grouping into integrated (n = 106) and non-integrated care group (n = 207) models. Univariate and multiple Cox regression were used to examine effect of care model, comorbidity, and complication event.One-year mortality in integrated and non-integrated patients was 4.7% and 14.0% respectively. After adjustments, patients in non-integrated care, have 2.89 times (95% confidence interval [CI] 1.07-7.81) likely to die 1-year after discharged.Patients had elevated comorbidity or postoperative complications contributed to the mortality. Our study found the effect of patients treated by integrated care models, compared with usual model, significantly reduced 1-year mortality rate. Appropriated treatment of comorbidities during hospitalization and after discharge is critical to post-surgical survival. The findings imply that the co-care for hip fracture of hip surgical patients with orthogeriatricians is strongly recommended, particularly for those with >3 comorbidities.

Transcription-independent and -dependent p53-mediated apoptosis in response to genotoxic and non-genotoxic stress.

We previously reported that p53-mediated apoptosis is determined by severity of DNA damage, not by the level of p53, in doxorubicin-treated prostate cancer cells. In addition to doxorubicin, our results here indicated that camptothecin and bortezomib, which are a topoisomerase 1 poison and a 26 S proteasome inhibitor, respectively, could also induce apoptosis in a p53-dependent manner in prostate cancer. Then, we examined whether p53-mediated apoptosis induced by genotoxic and non-genotoxic stress occur in the same or a different way. By using dominant negative p53 to compete with wild-type p53 in transcription activity, we demonstrated that p53-mediated apoptosis in response to doxorubicin- or camptothecin-induced genotoxic stress is transcription-independent. In contrast, p53-mediated apoptosis from bortezomib-induced stress is transcription-dependent. Interestingly, we also found that doxorubicin-induced p21 expression is activated by p53 in transcription-dependent manner, while camptothecin-induced p21 expression is p53-independent. We then investigated the p53 ratio of nucleus to cytosol corresponding to low and high dose doxorubicin, camptothecin, or bortezomib treatment. The results suggested that p53 translocation from cytoplasm to nucleus actively drives cells toward apoptosis in either transcription-dependent or -independent manner for responding to non-genotoxic or genotoxic stress, respectively.

The Safety of Continuing Antiplatelet Medication Among Elderly Patients Undergoing Urgent Hip Fracture Surgery.

Elderly patients with hip fractures who are receiving antiplatelet therapy are commonly encountered in clinical practice. This study sought to elucidate the safety of urgent hip surgery without termination of antiplatelet medication among patients taking a combination of aspirin and dipyridamole, aspirin alone, or dipyridamole alone. This retrospective cohort study included 176 patients 55 years or older who had uncomplicated hip fractures and underwent surgery within 48 hours after admission. On the basis of the preoperative medication regimen, the patients were divided into the following 4 groups: those receiving aspirin and dipyridamole combined (n=29); those receiving aspirin alone (n=63); those receiving dipyridamole alone (n=28); and those not receiving antiplatelet medication (n=56). Main outcomes, including total blood loss, transfusion rate, and 1-year mortality, were analyzed. There was no significant difference in total blood loss, transfusion rate, or 1-year mortality among the 4 groups. The group receiving aspirin and dipyridamole combined preoperatively had increased intraoperative blood loss (mean, 309.14±189.15 mL) compared with the group not receiving antiplatelet medication (mean, 214.64±119.21 mL; P=.005). There was no significant difference in the hazard ratio (P>.05) for 1-year mortality among the 4 groups after adjusting for confounding covariates, including age, sex, Charlson Comorbidity Index, and duration of hospital stay. Patients receiving antiplatelet medication, including aspirin, dipyridamole, or both, who have uncomplicated hip fractures may undergo urgent surgery without a significant difference in total blood loss, transfusion rate, or 1-year mortality compared with patients not receiving anti-platelet medication. [Orthopedics. 2019; 42(5):268-274.].