The m6A Reader YTHDF1 Accelerates the Osteogenesis of Bone Marrow Mesenchymal Stem Cells Partly via Activation of the Autophagy Signaling Pathway.

N6-methyladenosine (m6A) mRNA methylation has emerged as an important player in many biological processes by regulating gene expression. As a crucial reader, YTHDF1 usually improves the translation efficiency of its target mRNAs. However, its roles in bone marrow mesenchymal stem cells (BMSCs) osteogenesis remain largely unknown. Here, we reported that YTHDF1, an m6A reader, is highly expressed during osteogenic differentiation of BMSCs. Upregulation of YTHDF1 increased osteogenic differentiation and proliferation capacity of BMSCs. Accordingly, downregulation of YTHDF1 inhibited osteogenic differentiation and proliferation capacity. Possible underlying mechanisms were explored, and analysis revealed that YTHDF1 could affect autophagy levels, thus regulating osteogenesis of BMSCs. In an in vivo study, we found that upregulation of YTHDF1 accelerates fracture healing with elevated bone volume fraction and trabecular thickness. Taken together, our study revealed that m6A reader YTHDF1 accelerates osteogenic differentiation of BMSCs partly via the autophagy signaling pathway. These findings reveal a previously unrecognized mechanism involved in the regulation of BMSCs osteogenesis, providing new ideas and target sites for the treatment of fracture.

The orthodontic implant site-switching technique: a preliminary study in dogs.

BACKGROUND: To evaluate the quantity and quality of bone in the newly formed edentulous area produced by the orthodontic implant site-switching technique. METHODS: The bilateral maxillary first premolars of five beagle dogs were extracted and bone defects were created. The right and left sides of the maxilla were randomly divided into control and experimental sides. On the experimental side, the maxillary second premolar was mesially moved into the position of the missing first premolar. On the control side, the second maxillary premolar was extracted. Six months later, the beagles were euthanized. Microcomputer tomography was used to analyze bone microstructure parameters, alveolar bone height and alveolar bone width of the regenerated bone. Histological analysis was performed by staining tissue sections with toluidine blue. RESULTS: Median BV/TV values in the experimental group (81.78%) were significantly larger than those in the control group (35.67%; p = 0.04). Median Tb.Sp values in the experimental group (0.14 mm) were significantly lower than those in the control group (0.54 mm; p = 0.04). Median Tb.Th values in the experimental group (0.48 mm) were significantly higher than those in the control group (0.21 mm; p = 0.04). Median Tb.Pf values in the experimental group (0.65/mm) were significantly lower than those in the control group (3.15/mm; p = 0.04). There was no significant difference in the trabecular number (Tb.N) between the two groups (p = 0.23). The median alveolar bone height values in the experimental group (-0.81 mm) were significantly higher than those in the control group (-2.11 mm; p = 0.04) at a distance 5 mm from the mesial CEJ of the third premolar. The median alveolar bone height values in the experimental group (0.45 mm) were significantly higher than those in the control group (-1.70 mm; p = 0.04) at a distance 6 mm from the mesial CEJ of the third premolar. There was no significant difference in alveolar bone width when compared between the two groups (p > 0.05). CONCLUSIONS: The newly formed edentulous area created by orthodontic treatment had more compact and thicker trabeculae than the extraction socket. Furthermore, the newly formed edentulous area had a greater alveolar bone height available for the placement of implants.

Finite element analysis of sacral-alar-iliac screw fixation for sacroiliac joint dislocation.

The percutaneous sacroiliac (SI) screw is a common fixation option for posterior ring disruption in pelvic fractures. However, SI screw placement is difficult and can injure adjacent neurovascular structures. The sacral-alar-iliac screw (SAI) is a safe, reliable free-hand sacral pelvic fixation technique. To investigate the biomechanical stability of SAI for SI joint dislocation, finite element analysis was performed in unstable Tile-Type B and C pelvic ring injuries. The displacement in S1 (fixation of a unilateral S1 segment with one SI screw), TS1 (fixation of the S1 segment with a transsacra 1 screw), TS2 (fixation of the S2 segment with a transsacra 2 screw), S1AI, and S2AI exceeded the normal SI joint mobility. Sufficient stability after SI joint dislocation was obtained with (TS1 + TS2), (TS2 + S1), (S1AI + S2AI + rod), (S1AI + S2AI), and (S1 + S2AI + S1 pedicle) fixation. The TS1 + TS2 group had the smallest displacement and lowest peak screw stress, followed by (S1 + S2AI + S1 pedicle) placement. Our findings suggest that SAI screws are a valuable option for SI joint dislocation.

Reversing the imbalance in bone homeostasis via sustained release of SIRT-1 agonist to promote bone healing under osteoporotic condition.

The imbalance of bone homeostasis is the root cause of osteoporosis. However current therapeutic approaches mainly focus on either anabolic or catabolic pathways, which often fail to turn the imbalanced bone metabolism around. Herein we reported that a SIRT-1 agonist mediated molecular therapeutic strategy to reverse the imbalance in bone homeostasis by simultaneously regulating osteogenesis and osteoclastogenesis via locally sustained release of SRT2104 from mineral coated acellular matrix microparticles. Immobilization of SRT2104 on mineral coating (MAM/SRT) harnessing their electrostatic interactions resulted in sustained release of SIRT-1 agonist for over 30 days. MAM/SRT not only enhanced osteogenic differentiation and mineralization, but also attenuated the formation and function of excessive osteoclasts via integrating multiple vital upstream signals (ß-catenin, FoxOs, Runx2, NFATc1, etc.) in vitro. Osteoporosis animal model also validated that it accelerated osteoporotic bone healing and improved osseointegration of the surrounding bone. Overall, our work proposes a promising strategy to treat osteoporotic bone defects by reversing the imbalance in bone homeostasis using designated small molecule drug delivery systems.

Parkin Inhibits RANKL-Induced Osteoclastogenesis and Ovariectomy-Induced Bone Loss.

Osteoporosis and osteoporotic fractures comprise a substantial health and socioeconomic burden. The leading cause of osteoporosis is an imbalance in bone formation and bone resorption caused by hyperactive osteoclasts. Therefore, a new strategy to suppress osteoclastogenesis is needed. Parkin is likely closely associated with bone metabolism, although its role in osteoclastogenesis is unclear. In this study, the Parkin protein inhibited the receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast formation, osteoclast-specific gene expression, F-actin ring formation, and bone resorption pit formation in vitro. Moreover, depletion of Parkin enhanced RANKL-induced osteoclast formation, osteoclast-specific gene expression, F-actin ring formation, and bone resorption pit formation. Reactive oxygen species (ROS) activity was suppressed, while autophagy was upregulated with the presence of the Parkin protein. ROS activity was upregulated and autophagy was decreased due to Parkin knockdown. In addition, intravenous administration of Parkin rescued ovariectomy-induced bone loss and reduced osteoclastogenesis in vivo. Collectively, Parkin has therapeutic potential for diseases associated with overactive osteoclasts.

The role of the Smad2/3/4 signaling pathway in osteogenic differentiation regulation by ClC-3 chloride channels in MC3T3-E1 cells.

BACKGROUND: ClC-3 chloride channels promote osteogenic differentiation. Transforming growth factor-ß1 (TGF-ß1) and its receptors are closely related to ClC-3 chloride channels, and canonical TGF-ß1 signaling is largely mediated by Smad proteins. The current study aimed to explore the role of the Smad2/3/4 signaling pathway in the mechanism by which ClC-3 chloride channels regulate osteogenic differentiation in osteoblasts. METHODS: First, real-time PCR and western blotting were used to detect the expression of Smad and mitogen-activated protein kinase (MAPK) proteins in response to ClC-3 chloride channels. Second, immunocytochemistry, coimmunoprecipitation (Co-IP) and immunofluorescence analyses were conducted to assess formation of the Smad2/3/4 complex and its translocation to the nucleus. Finally, markers of osteogenic differentiation were determined by real-time PCR, western blotting, ALP assays and Alizarin Red S staining. RESULTS: ClC-3 chloride channels knockdown led to increased expression of Smad2/3 but no significant change in p38 or Erk1/2. Furthermore, ClC-3 chloride channels knockdown resulted in increases in the formation of the Smad2/3/4 complex and its translocation to the nucleus. In contrast, the inhibition of TGF-ß1 receptors decreased the expression of Smad2, Smad3, p38, and Erk1/2 and the formation of the Smad2/3/4 complex. Finally, the expression of osteogenesis-related markers were decreased upon ClC-3 and Smad2/3/4 knockdown, but the degree to which these parameters were altered was decreased upon the knockdown of ClC-3 and Smad2/3/4 together compared to independent knockdown of ClC-3 or Smad2/3/4. CONCLUSIONS: The Smad2/3 proteins respond to changes in ClC-3 chloride channels. The Smad2/3/4 signaling pathway inhibits osteogenic differentiation regulation by ClC-3 chloride channels in MC3T3-E1 cells.

Vascular Derived ECM Improves Therapeutic Index of BMP-2 and Drives Vascularized Bone Regeneration.

Vascularized osteogenesis is essential for successful bone regeneration, yet its realization during large size bone defect healing remains challenging due to the difficulty to couple multiple biological processes. Herein, harnessing the intrinsic angiogenic potential of vascular derived extracellular matrix (vECM) and its specific affinity to growth factors, a vECM/GelMA based hybrid hydrogel delivery system is constructed to achieve optimized bone morphogenetic protein-2 (BMP-2) therapeutic index and provide intrinsic angiogenic induction during bone healing. The incorporation of vECM not only effectively regulates BMP-2 kinetics to match the bone healing timeframe, but also promotes angiogenesis both in vitro and in vivo. In vivo results also show that vECM-mediated BMP-2 release remarkably enhances vascularized bone formation for critical size bone defects. In particular, blood vessel ingrowth stained with CD31 marker in the defect area is substantially encouraged over the course of healing, suggesting incorporation of vECM served roles in both angiogenesis and osteogenesis. Thus, the authors' study exemplifies that affinity of growth factor towards ECM may be a promising strategy to be leveraged to develop sophisticated delivery systems endowed with desirable properties for regenerative medicine applications.

a-PET and Weakened Triplet-Triplet Annihilation Self-Quenching Effects in Benzo-21-Crown-7-Functionalized Diiodo-BODIPY.

Weakening the triplet-triplet annihilation (TTA) self-quenching effect induced by sensitizers remains a tremendous challenge due to the very few investigations carried out on them. Herein, benzo-21-crown-7 (B21C7)-functionalized 2,6-diiodo-1,3,5,7-tetramethyl-8-phenyl-4,4-difluoroboradiazaindacene (DIBDP) was synthesized to investigate the influences of huge bulks and electron-rich cavities of B21C7 moieties on the fluorescence emission and triplet-state lifetimes of DIBDP moieties. Density functional theory (DFT)/time-dependent DFT (TDDFT) computable results preliminarily predicted that B21C7 moieties had influences on the fluorescence emissions of DIBDP moieties but not on their localization of triplet states of B21C7-functionalized DIBDP (B21C7-DIBDP). The UV-vis absorption spectra, fluorescence emission spectra, and cyclic voltammograms verified that there was an electron-transfer process from the B21C7 moiety to the DIBDP moiety in B21C7-DIBDP. However, the calculated results of ΔG CS and E CS values and nanosecond time-resolved transient absorption spectra demonstrated that the electron-transfer process from the B21C7 moiety to the DIBDP moiety in B21C7-DIBDP had direct influences on the fluorescence emission of DIBDP moieties but not on the triplet states of DIBDP moieties. The experimental values of triplet-state lifetimes of B21C7-DIBDP were obviously longer than those of DIBDP at a high concentration (1.0 × 10-5 M); however, the fitted values of intrinsic triplet-state lifetimes of B21C7-DIBDP were slightly greater than those of DIBDP in the same solvent. These results demonstrated that the steric hindrance of B21C7 moieties could weaken the TTA self-quenching effect of DIBDP moieties at a high concentration and the a-PET effect induced a proportion of the produced singlet states of DIBDP moieties and could not emit fluorescence in the form of radiation transition but they could be transformed into triplet states through intersystem crossing (ISC) processes due to the iodine atoms in the DIBDP moiety. The stronger a-PET effects in polar solvents induced smaller fluorescence quantum yields so that more singlet states of DIBDP moieties were transformed into triplet states to weaken the TTA self-quenching effects.

Transformation of acellular dermis matrix with dicalcium phosphate into 3D porous scaffold for bone regeneration.

Animal derived biomaterials have attracted much attentions in treating large size bone defect due to their excellent biocompatibility and potent bioactivities offered by the biomacromolecules and growth factors contained in these materials. Dermis-derived matrix (ADM) has been used as skin grafts and wound dressings for decades, however its application in bone tissue engineering has been largely limited as ADM possesses a dense structure which does not support bone tissue ingrowth. Recently, we have successfully fabricated porous scaffold structure using an ADM with the aid of micronization technique. When integrated with inorganic components such as calcium phosphate, ADM could be transformed to bone graft substitutes with desirable osteogenic properties. While purified and chemically cross-linked collagen has lost its natural structure, our ADM successfully preserved natural tropocollagen structure, as well as other bioactive components. A composite scaffold was fabricated by incorporating dicalcium phosphate (DCP) microparticles into ADM microfibers and freeze-dried to form a highly porous structure. Unlike conventional ADM materials, this scaffold possesses high porosity with interconnected pores. More importantly, our evaluation data demonstrated that it performed much more effective in treating critical bone defects in comparison with best commercial product on the market. In a head-to-head comparison with a commercial bone graft material Bongold®, the ADM/DCP scaffold showed superior osteogenic capacity by filling the defect with well-organized new bone tissue in a rabbit radius segmental defect model. Put together, our results exhibited a novel bone graft substitute was developed by circumventing processing barriers associated with natural ADM, which offers another novel bone graft substitute for bone regeneration.

Low-dose IL-34 has no effect on osteoclastogenesis but promotes osteogenesis of hBMSCs partly via activation of the PI3K/AKT and ERK signaling pathways.

BACKGROUND: Inflammatory microenvironment is significant to the differentiation and function of mesenchymal stem cells (MSCs). It evidentially influences the osteoblastogenesis of MSCs. IL-34, a newly discovered cytokine, playing a key role in metabolism. However, the research on its functional role in the osteogenesis of MSCs was rarely reported. Here, we described the regulatory effects of low-dose IL-34 on both osteoblastogenesis and osteoclastogenesis. METHODS: We performed the osteogenic effects of hBMSCs by exogenous and overexpressed IL-34 in vitro, so were the osteoclastogenesis effects of mBMMs by extracellular IL-34. CCK-8 was used to assess the effect of IL-34 on the viability of hBMSCs and mBMMs. ALP, ARS, and TRAP staining was used to evaluate ALP activity, mineral deposition, and osteoclastogenesis, respectively. qRT-PCR and Western blotting analysis were performed to detect the expression of target genes and proteins. ELISA was used to evaluate the concentrations of IL-34. In vivo, a rat tibial osteotomy model and an OVX model were established. Radiographic analysis and histological evaluation were performed to confirm the therapeutic effects of IL-34 in fracture healing and osteoporosis. Statistical differences were evaluated by two-tailed Student's t test, one-way ANOVA with Bonferroni's post hoc test, and two-way ANOVA with Bonferroni multiple comparisons post hoc test in the comparison of 2 groups, more than 2 groups, and different time points of treated groups, respectively. RESULTS: Promoted osteoblastogenesis of hBMSCs was observed after treated by exogenous or overexpressed IL-34 in vitro, confirmed by increased mineral deposits and ALP activity. Furthermore, exogenous or overexpressed IL-34 enhanced the expression of p-AKT and p-ERK. The specific AKT and ERK signaling pathway inhibitors suppressed the enhancement of osteoblastogenesis induced by IL-34. In a rat tibial osteotomy model, imaging and histological analyses testified the local injection of exogenous IL-34 improved bone healing. However, the additional IL-34 has no influence on both osteoclastogenesis of mBMMs in vitro and osteoporosis of OVX model of rat in vivo. CONCLUSIONS: Collectively, our study demonstrate that low-dose IL-34 regulates osteogenesis of hBMSCs partly via the PIK/AKT and ERK signaling pathway and enhances fracture healing, with neither promoting nor preventing osteoclastogenesis in vitro and osteoporosis in vivo.

A trilogy antimicrobial strategy for multiple infections of orthopedic implants throughout their life cycle.

Bacteria-associated infection represents one of the major threats for orthopedic implants failure during their life cycles. However, ordinary antimicrobial treatments usually failed to combat multiple waves of infections during arthroplasty and prosthesis revisions etc. As these incidents could easily introduce new microbial pathogens in/onto the implants. Herein, we demonstrate that an antimicrobial trilogy strategy incorporating a sophisticated multilayered coating system leveraging multiple ion exchange mechanisms and fine nanotopography tuning, could effectively eradicate bacterial infection at various stages of implantation. Early stage bacteriostatic effect was realized via nano-topological structure of top mineral coating. Antibacterial effect at intermediate stage was mediated by sustained release of zinc ions from doped CaP coating. Strong antibacterial potency was validated at 4 weeks post implantation via an implanted model in vivo. Finally, the underlying zinc titanate fiber network enabled a long-term contact and release effect of residual zinc, which maintained a strong antibacterial ability against both Staphylococcus aureus and Escherichia coli even after the removal of top layer coating. Moreover, sustained release of Sr2+ and Zn2+ during CaP coating degradation substantially promoted implant osseointegration even under an infectious environment by showing more peri-implant new bone formation and substantially improved bone-implant bonding strength.

The Role of Forkhead Box Family in Bone Metabolism and Diseases.

Forkhead box (Fox) family, an evolutionarily conserved family of transcription factors carrying the "Forkhead" motif, plays an indispensable role in human health and disease. Fox family genes are involved in cell differentiation, proliferation and apoptosis, embryonic development, aging, glucose and lipid metabolism, and immune regulation. The regulatory role of the Fox family in the context of bone metabolism and orthopedic diseases is an emerging research hotspot. In this review, we highlight the major molecular mechanisms underlying the regulatory role of Fox factors in bone metabolism, bone development, bone homeostasis, and bone diseases associated with inhibition or upregulation of Fox factors. In addition, we discuss the emerging evidence in the realm of Fox factor-based therapeutics.

Utility of Air Bladder-Derived Nanostructured ECM for Tissue Regeneration.

Exploration for ideal bone regeneration materials still remains a hot research topic due to the unmet clinical challenge of large bone defect healing. Bone grafting materials have gradually evolved from single component to multiple-component composite, but their functions during bone healing still only regulate one or two biological processes. Therefore, there is an urgent need to develop novel materials with more complex composition, which convey multiple biological functions during bone regeneration. Here, we report an naturally nanostructured ECM based composite scaffold derived from fish air bladder and combined with dicalcium phosphate (DCP) microparticles to form a new type of bone grafting material. The DCP/acellular tissue matrix (DCP/ATM) scaffold demonstrated porous structure with porosity over 65% and great capability of absorbing water and other biologics. In vitro cell culture study showed that DCP/ATM scaffold could better support osteoblast proliferation and differentiation in comparison with DCP/ADC made from acid extracted fish collagen. Moreover, DCP/ATM also demonstrated more potent bone regenerative properties in a rat calvarial defect model, indicating incorporation of ECM based matrix in the scaffolds could better support bone formation. Taken together, this study demonstrates a new avenue toward the development of new type of bone regeneration biomaterial utilizing ECM as its key components.

Upregulation of Parkin Accelerates Osteoblastic Differentiation of Bone Marrow-Derived Mesenchymal Stem Cells and Bone Regeneration by Enhancing Autophagy and ß-Catenin Signaling.

Osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) plays a key role in bone formation. Parkin, an E3 ubiquitin ligase, related to Parkinson's disease and aging. Previous studies have indicated that Parkinson's disease have a higher risk of osteoporotic fracture. To investigate the effects and underlying mechanism of Parkin in the osteogenic differentiation of BMSCs, osteogenic differentiation was analyzed following upregulation or downregulation of Parkin. We found that Parkin was increased during differentiation. Parkin overexpression enhanced osteo-specific markers, and downregulation of Parkin mitigated osteo-specific markers. Moreover, upregulation of Parkin promoted ß-catenin expression and autophagy and vice versa. The upregulation of ß-catenin enhanced autophagy, and the activation of autophagy also increased the expression of ß-catenin in Parkin-downregulated BMSCs. Parkin-overexpressed cell sheets accelerated bone healing in a tibial fracture model. Based on these results, we concluded that Parkin meditates osteoblastic differentiation of BMSCs via ß-catenin and autophagy signaling.

2-methylbenzoyl berbamine, a multi-targeted inhibitor, suppresses the growth of human osteosarcoma through disabling NF-κB, ERK and AKT signaling networks.

Osteosarcoma is the most common malignant bone tumor in children and young adults, and it has a survival rate of only 60% with current cytotoxic chemotherapy combined with aggressive surgery. The aim of this study was to evaluate the therapeutic efficacy of the berbamine derivative 2-methylbenzoyl berbamine (BBD24) for osteosarcoma in vitro and in vivo. We used human osteosarcoma cell lines, primary osteosarcoma cells and mouse models to evaluate the inhibitory effects of BBD24 on osteosarcoma and to determine the molecular mechanism. Our results showed that BBD24 inhibited the growth of the human osteosarcoma cell lines HOS and MG63 in a time- and dose-dependent manner. BBD24 also exhibited significant inhibitory effects on primary osteosarcoma cells. In contrast, BBD24 did not affect normal blood cells under the same conditions. Treatment with BBD24 induced apoptosis, necrosis and autophagy in osteosarcoma cells. Western blot analysis revealed that BBD24 activated the caspase-dependent pathway and downregulated the NF-kB, AKT, and ERK pathways. Finally, BBD24 treatment induced a significant inhibitory effect on the growth of osteosarcoma in nude mice. Our findings indicate that BBD24 is a multitarget inhibitor and may represent a new type of anticancer agent for osteosarcoma treatment.

Epidemiologic characteristics of traumatic fractures in elderly patients during the outbreak of coronavirus disease 2019 in China.

PURPOSE: This study aimed to describe the epidemiologic characteristics of fracture in the elderly during the COVID-19. METHODS: This was a retrospective multi-centre study, which included patients who sustained fractures between 20 January and 19 February 2020. The collected data included patients' demographics (age and gender), injury-related (injury type, fracture location, injury mechanism, places where fracture occurred), and treatment modality. SPSS 23.0 was used to describe the data and perform some analysis. RESULTS: A total of 436 patients with 453 fractures were included; there were 153 males and 283 females, with an average age of 76.2 years (standard deviation, SD, 7.7 years; 65 to 105). For either males or females, 70-74 years was the most commonly involved age group. A total of 317 (72.7%) patients had their fractures occurring at home. Among 453 fractures, there were 264 (58.3%) hip fractures, accounting for 58.3%. Fall from standing height was the most common cause of fracture, making a proportion of 89.4% (405/453). Most fractures (95.8%, 434/453) were treated surgically, and 4.2% (19/453) were treated by plaster fixation or traction. Open reduction and internal fixation (ORIF) was the most used surgical method, taking a proportion of 49.2% (223/453). CONCLUSION: These findings highlighted the importance of primary prevention (home prevention) measures and could be used for references for individuals, health care providers, or health administrative department during the global pandemic of COVID-19.

Loss of TIMP3 expression induces inflammation, matrix degradation, and vascular ingrowth in nucleus pulposus: A new mechanism of intervertebral disc degeneration.

Low back pain (LBP) is one of the most common complains in orthopedic outpatient department and intervertebral disc degeneration (IDD) is one of the most important reasons of LBP. The mechanisms of IDD contain a complex biochemical cascade which includes inflammation, vascular ingrowth, and results in degradation of matrix. In our study, we used both in vitro and in vivo models to investigate the relation between tissue inhibitor of metalloproteinase-3 (TIMP3) expression and IDD. Loss of TIMP3 expression was found in degenerative intervertebral disc (IVD), this change of expression was closely related with the dephosphorylation of smad2/3. Overexpression of TIMP3 significantly inhibited the release of TNF-α and matrix degradation induced by Lipopolysaccharide. Vascular ingrowth was also suppressed by TIMP3 in the in vitro and in vivo models. Further, animal experiments confirmed that the degeneration of IVD was reduced after overexpression of TIMP3 in nucleus pulposus. Taken together, our results indicated TIMP-3 might play an important role in the pathogenesis of IDD and therefore be a potential therapeutic target in the future.

Weight changes after total knee arthroplasty in Chinese patients: a matched cohort study regarding predictors and outcomes.

BACKGROUND: The purpose of this study was to compare 2-year BMI changes between patients undergoing simultaneous bilateral total knee arthroplasty (TKA), staged bilateral TKA, and unilateral TKA. We also sought to determine the predictors of weight change and whether clinically meaningful weight changes affected outcomes. PATIENTS AND METHODS: This retrospective, single-institution study included 202 Chinese patients who received simultaneously bilateral TKA, staged bilateral TKA, or unilateral TKA from 2008 to 2015. There were 49 simultaneous bilateral TKAs, 52 staged bilateral TKAs, and a matched 101 unilateral TKAs. RESULTS: 66.8% (135/202) of patients lost weight after TKA surgery. However, 20.7% (42/202) of patients experienced clinically meaningful weight loss (a BMI decrease of more than 5%). Paired t test showed that 2-year BMI was significantly lower than preoperative BMI (p < 0.001). Weight loss was significantly different between the surgical strategy (p < 0.001). Preoperative BMI and age were predictive of clinically significant weight loss or gain (p < 0.05). Multiple linear regression showed that post-operative weight loss was associated with better Western Ontario and McMaster Universities Osteoarthritis Index and SF-36 scores (p < 0.001). CONCLUSION: Patients after TKA experience weight loss. Age and preoperative BMI predict clinically meaningful weight change. Simultaneous bilateral TKA is associated with higher likelihood of weight loss. Clinically meaningful weight loss experiences better patient-reported outcomes.

Bergenin Activates SIRT1 as a Novel Therapeutic Agent for Osteogenesis of Bone Mesenchymal Stem Cells.

Bone mesenchymal stem cells (BMSCs) are important candidates for bone regeneration. The role of Bergenin, a C-glucoside of 4-O-methyl gallic acid obtained from the species, Bergenia, in BMSC osteogenesis has not yet been elucidated. We therefore investigated the effects of Bergenin on the osteogenesis of BMSCs and found that Bergenin enhanced osteoblast-specific markers and downregulated the adipocyte-specific markers in vitro. Furthermore, using a rat calvarial defect model, we found that Bergenin significantly improved bone healing, as determined by imaging and histological analyses. Moreover, it also upregulated SIRT1 expression. A SIRT1 inhibitor (EX 527) decreased the enhanced bone mineral formation caused by Bergenin. Taken together, these findings show that Bergenin accelerated the osteogenic differentiation of BMSCs, at least partly through the activation of SIRT1.

Bioengineering application using co-cultured mesenchymal stem cells and preosteoclasts may effectively accelerate fracture healing.

Fracture non-union is the most challenging complication following fracture injuries. Despite ongoing improvements in the surgical technique and implant design, the treatment efficacy of fracture non-union is still far from satisfactory and currently there is no optimal solution. Of all of the methods used for the treatment of non-union, bone tissue bioengineering using scaffolds and mesenchymal stem cells (MSCs) is the most widely studied and has emerged as a promising approach to address these challenges. However, there are several critical limitations, such as the low survival rate of MSCs under an inflammatory, ischemic environment. Accumulating studies have demonstrated that preosteoclasts not only play a role in the remodeling of the callus, but also participate in the entire process of fracture repair. The close crosstalk between preosteoclasts and MSCs stimulates the recruitment, proliferation, and differentiation of osteoblasts and improves the osteogenic differentiation of MSCs. With no in vivo study reported thus far, we hypothesize that the administration of preosteoclasts together with MSCs at a certain ratio may effectively accelerate fracture healing and provide a new and promising therapeutic strategy for the clinical management of fracture non-union.