Life Course Epidemiology of Hip Osteoarthritis in Japan: A Multicenter, Cross-Sectional Study.

BACKGROUND: The incidence of developmental dysplasia of the hip (DDH) in Japanese newborns has reduced drastically following a primary prevention campaign initiated around 1972 to 1973; this perinatal education campaign promoted maintaining the hips of newborns in the naturally flexed-leg position. The purpose of the present study was to describe the life course epidemiology of hip osteoarthritis (OA) in adolescent and adult patients and to assess its association with exposure to the primary prevention campaign for DDH. METHODS: We included new patients with hip OA diagnosed from January 1, 2022, to December 31, 2022, at 12 core hospitals (8 special-function hospitals and 4 regional medical care support hospitals). The trend in the percentage of hips with a history of DDH treatment in childhood was estimated with use of a centered moving average using the birth year of the patient. We compared the prevalence of severe subluxation (Crowe type II, III, or IV) between patients with secondary hip OA due to hip dysplasia who were born in or before 1972 and those who were born in or after 1973. RESULTS: Overall, 1,095 patients (1,381 hips) were included. The mean age at the time of the survey was 63.5 years (range, 15 to 95 years). A total of 795 patients (1,019 hips; 73.8% of hips) were diagnosed with secondary OA due to hip dysplasia. Approximately 13% to 15% of hips among patients born from 1963 to 1972 had a history of DDH treatment in childhood; however, the percentage decreased among patients born in or after 1973. The prevalence of severe subluxation (Crowe type II, III, or IV) among patients born in or after 1973 was 2.4%, which was significantly less than that among patients born in or before 1972 (11.1%; odds ratio, 0.20; p < 0.001). CONCLUSIONS: As of 2022, secondary hip OA due to hip dysplasia is still responsible for most new cases of adolescent and adult hip OA seen in core hospitals in Japan. However, the perinatal education campaign initiated 50 years ago, which utilized a population approach and advocated for maintaining the hips of newborns in the naturally flexed-leg position, may have improved the environmental factors of DDH, as indicated by the apparently reduced need for treatment of DDH in childhood and the associated severe subluxation. This may result in a reduced need for challenging hip surgery later in life. LEVEL OF EVIDENCE: Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

Effect of rifampicin administration on CYP induction in a dermatomyositis patient with vasospastic angina attributable to nilmatrelvir/ritonavir-induced blood tacrolimus elevation: A case report.

Ritonavir (RTV), which is used in combination with nilmatrelvir (NMV) to treat coronavirus disease 2019 (COVID-19), inhibits cytochrome P450 (CYP) 3A, thereby increasing blood tacrolimus (TAC) levels through a drug-drug interaction (DDI). We experienced a case in which a DDI between the two drugs led to markedly increased blood TAC levels, resulting in vasospastic angina (VSA) and acute kidney injury (AKI). Rifampicin (RFP) was administered to induce CYP3A and promote TAC metabolism. A 60-year-old man with dermatomyositis who was taking 3 mg/day TAC contracted COVID-19. The patient started oral NMV/RTV therapy, and he was admitted to the hospital after 4 days because of chest pain and AKI. On day 5, his blood TAC level increased markedly to 119.8 ng/mL. RFP 600 mg was administered once daily for 3 days, and his blood TAC level decreased to the therapeutic range of 9.6 ng/mL on day 9, leading to AKI improvement. Transient complete atrioventricular block and nonsustained ventricular tachycardia were present during chest pain. In the coronary spasm provocation test, complete occlusion was observed in the right coronary artery, leading to a diagnosis of VSA. VSA and AKI are possible side effects of high blood TAC levels caused by DDI, and attention should be paid to cardiovascular side effects such as VSA and AKI associated with increased blood levels of TAC when it is used together with NMV/RTV. When blood levels of TAC increase, oral RFP can rapidly decrease TAC blood levels and potentially reduce its toxicity.

A laser guide technique: a novel method for accurate acetabular cup alignment in total hip arthroplasty.

For accurate cup alignment without navigation in total hip arthroplasty (THA), we developed a "laser guide technique." The major purposes of this paper are to introduce the technique and compare its accuracy with a conventional manual technique. As a clinical outcome, the dislocation rate was reviewed. Our laser guide technique, which includes preoperative postural adjustment and intraoperative angular reference, has been detailed in the manuscript. 599 hips in 523 patients who underwent primary THA with piriformis-sparing posterolateral approach in April 2010-March 2016 were reviewed. Patients were divided into three groups: conventional group (135 hips), laser guide group (80 hips), and laser + radiographic alignment guide group (384 hips). Radiographic inclination (RI) and radiographic anteversion (RA) errors were evaluated. The dislocation rate was reviewed in 540 hips in 476 patients who were followed up > 2 years postoperatively. Absolute values of the RI/RA error in the three groups were 5.3° ± 4.0°/6.5° ± 4.5°, 4.0° ± 2.8°/4.9° ± 4.4°, and 3.3° ± 2.6°/3.6° ± 2.8°, respectively, indicating substantially enhanced accuracy with laser and radiographic alignment guide. The dislocation rates were 2.5% (3/119) and 0.2% (1/421) in the conventional and laser groups, respectively. Our novel laser guide technique considerably enhanced cup alignment accuracy, suggesting its potential applicability for THA in the lateral decubitus position.

Mesenchymal Stem Cells and NF-κB Sensing Interleukin-4 Over-Expressing Mesenchymal Stem Cells Are Equally Effective in Mitigating Particle-Associated Chronic Inflammatory Bone Loss in Mice.

Wear particles from total joint arthroplasties (TJAs) induce chronic inflammation, macrophage infiltration and lead to bone loss by promoting bone destruction and inhibiting bone formation. Inhibition of particle-associated chronic inflammation and the associated bone loss is critical to the success and survivorship of TJAs. The purpose of this study is to test the hypothesis that polyethylene particle induced chronic inflammatory bone loss could be suppressed by local injection of NF-κB sensing Interleukin-4 (IL-4) over-expressing MSCs using the murine continuous polyethylene particle infusion model. The animal model was generated with continuous infusion of polyethylene particles into the intramedullary space of the femur for 6 weeks. Cells were locally injected into the intramedullary space 3 weeks after the primary surgery. Femurs were collected 6 weeks after the primary surgery. Micro-computational tomography (µCT), histochemical and immunohistochemical analyses were performed. Particle-infusion resulted in a prolonged pro-inflammatory M1 macrophage dominated phenotype and a decrease of the anti-inflammatory M2 macrophage phenotype, an increase in TRAP positive osteoclasts, and lower alkaline phosphatase staining area and bone mineral density, indicating chronic particle-associated inflammatory bone loss. Local injection of MSCs or NF-κB sensing IL-4 over-expressing MSCs reversed the particle-associated chronic inflammatory bone loss and facilitated bone healing. These results demonstrated that local inflammatory bone loss can be effectively modulated via MSC-based treatments, which could be an efficacious therapeutic strategy for periprosthetic osteolysis.

Computer-aided diagnosis with a convolutional neural network algorithm for automated detection of urinary tract stones on plain X-ray.

BACKGROUND: Recent increased use of medical images induces further burden of their interpretation for physicians. A plain X-ray is a low-cost examination that has low-dose radiation exposure and high availability, although diagnosing urolithiasis using this method is not always easy. Since the advent of a convolutional neural network via deep learning in the 2000s, computer-aided diagnosis (CAD) has had a great impact on automatic image analysis in the urological field. The objective of our study was to develop a CAD system with deep learning architecture to detect urinary tract stones on a plain X-ray and to evaluate the model's accuracy. METHODS: We collected plain X-ray images of 1017 patients with a radio-opaque upper urinary tract stone. X-ray images (n = 827 and 190) were used as the training and test data, respectively. We used a 17-layer Residual Network as a convolutional neural network architecture for patch-wise training. The training data were repeatedly used until the best model accuracy was achieved within 300 runs. The F score, which is a harmonic mean of the sensitivity and positive predictive value (PPV) and represents the balance of the accuracy, was measured to evaluate the model's accuracy. RESULTS: Using deep learning, we developed a CAD model that needed 110 ms to provide an answer for each X-ray image. The best F score was 0.752, and the sensitivity and PPV were 0.872 and 0.662, respectively. When limited to a proximal ureter stone, the sensitivity and PPV were 0.925 and 0.876, respectively, and they were the lowest at mid-ureter. CONCLUSION: CAD of a plain X-ray may be a promising method to detect radio-opaque urinary tract stones with satisfactory sensitivity although the PPV could still be improved. The CAD model detects urinary tract stones quickly and automatically and has the potential to become a helpful screening modality especially for primary care physicians for diagnosing urolithiasis. Further study using a higher volume of data would improve the diagnostic performance of CAD models to detect urinary tract stones on a plain X-ray.

Different Effects of Intramedullary Injection of Mesenchymal Stem Cells During the Acute vs. Chronic Inflammatory Phase on Bone Healing in the Murine Continuous Polyethylene Particle Infusion Model.

Chronic inflammation is a common feature in many diseases of different organ systems, including bone. However, there are few interventions to mitigate chronic inflammation and preserve host tissue. Previous in vitro studies demonstrated that preconditioning of mesenchymal stem cells (pMSCs) using lipopolysaccharide and tumor necrosis factor-α polarized macrophages from a pro-inflammatory to an anti-inflammatory phenotype and increased osteogenesis compared to unaltered MSCs. In the current study, we investigated the local injection of MSCs or pMSCs during the acute versus chronic inflammatory phase in a murine model of inflammation of bone: the continuous femoral intramedullary polyethylene particle infusion model. Chronic inflammation due to contaminated polyethylene particles decreased bone mineral density and increased osteoclast-like cells positively stained with leukocyte tartrate resistant acid phosphatase (TRAP) staining, and resulted in a sustained M1 pro-inflammatory macrophage phenotype and a decreased M2 anti-inflammatory phenotype. Local injection of MSCs or pMSCs during the chronic inflammatory phase reversed these findings. Conversely, immediate local injection of pMSCs during the acute inflammatory phase impaired bone healing, probably by mitigating the mandatory acute inflammatory reaction. These results suggest that the timing of interventions to facilitate bone healing by modulating inflammation is critical to the outcome. Interventions to facilitate bone healing by modulating acute inflammation should be prudently applied, as this phase of bone healing is temporally sensitive. Alternatively, local injection of MSCs or pMSCs during the chronic inflammatory phase may be a potential intervention to mitigate the adverse effects of contaminated particles on bone.

Suppression of NF-κB-induced chronic inflammation mitigates inflammatory osteolysis in the murine continuous polyethylene particle infusion model.

Wear particle-associated bone loss (periprosthetic osteolysis) constrains the longevity of total joint arthroplasty (TJA). Wear particles induce a prolonged upregulation of nuclear factor kappa B (NF-κB) signaling in macrophages and osteoclasts. Synthetic double-stranded oligodeoxynucleotides (ODNs) can prevent the binding of NF-κB to the promoter regions of targeted genes and inhibit genetic activation. We tested the hypothesis that polyethylene-particle induced chronic inflammatory bone loss could be suppressed by local delivery of NF-κB decoy ODNs in murine in vivo model. Polyethylene particles were continuously infused into the medullary cavity of the distal femur for 6 weeks to induce chronic inflammation, and micro-computational tomography and immunohistochemical analysis were performed. Particle-induced chronic inflammation resulted in lower BMD values, an increase in osteoclastogenesis and nuclear translocation of p65, a prolonged M1 pro-inflammatory macrophage phenotype, and a decrease of M2 anti-inflammatory macrophage phenotype. Delayed timing of local infusion of NF-κB decoy ODN for the last 3 weeks reversed polyethylene-particle associated chronic inflammatory bone loss and facilitated bone healing. This study demonstrated that polyethylene-particle associated chronic inflammatory osteolysis can be effectively modulated via interference with the NF-κB pathway; this minimally invasive intervention could potentially be an efficacious therapeutic strategy for periprosthetic osteolysis after TJA.

Successful outcomes of endoscopic lithotripsy in completely bedridden patients with symptomatic urinary calculi.

Due to the aging population, the number of completely bedridden individuals is expected to increase, and such individuals are at high risk of developing urinary calculi. This retrospective study included 32 consecutive bedridden patients, who had undergone endoscopic lithotripsy between 2010 and 2019, and aimed to identify the treatment outcomes of endoscopic lithotripsy for bedridden patients. A total of 45 endoscopic lithotripsies were performed to treat stones (median cumulative diameter, 24 mm). The stone-free rate (SFR) < 4 mm and complete SFR (0 mm) were achieved in 81% and 63% of patients, respectively. Postoperatively, 10 patients (22%) developed symptoms of systemic inflammatory response syndrome, and three patients (7%) had bloodstream infections. Except for one patient (3%) having a retained ureteral stent ultimately died from septic shock, drainage tube-free discharge was achieved in all patients. The 2-year cumulative incidence of stone-related events, and overall mortality rate, were 18% and 27%, respectively. Endoscopic lithotripsy is well tolerated and is associated with a high success rate, even with severe comorbidities and a relatively large stone burden. Physicians should consider performing endoscopic lithotripsy in bedridden patients with symptomatic urinary calculi regardless of their relatively short life expectancy and the remote risk of perioperative mortality.

Interleukin-4 overexpressing mesenchymal stem cells within gelatin-based microribbon hydrogels enhance bone healing in a murine long bone critical-size defect model.

Mesenchymal stem cell (MSC)-based therapy is a promising strategy for bone repair. Furthermore, the innate immune system, and specifically macrophages, plays a crucial role in the differentiation and activation of MSCs. The anti-inflammatory cytokine Interleukin-4 (IL-4) converts pro-inflammatory M1 macrophages into a tissue regenerative M2 phenotype, which enhances MSC differentiation and function. We developed lentivirus-transduced IL-4 overexpressing MSCs (IL-4 MSCs) that continuously produce IL-4 and polarize macrophages toward an M2 phenotype. In the current study, we investigated the potential of IL-4 MSCs delivered using a macroporous gelatin-based microribbon (µRB) scaffold for healing of critical-size long bone defects in Mice. IL-4 MSCs within µRBs enhanced M2 marker expression without inhibiting M1 marker expression in the early phase, and increased macrophage migration into the scaffold. Six weeks after establishing the bone defect, IL-4 MSCs within µRBs enhanced bone formation and helped bridge the long bone defect. IL-4 MSCs delivered using macroporous µRB scaffold is potentially a valuable strategy for the treatment of critical-size long bone defects.

Increased NF-kB activity in osteoprogenitor-lineage cells impairs the balance of bone versus fat in the marrow of skeletally mature mice.

"Senile osteoporosis" is defined as significant aging-associated bone loss, and is accompanied by increased fat in the bone marrow. The proportion of adipocytes in bone marrow is inversely correlated with bone formation, and is associated with increased risk of fracture. NF-κB is a transcription factor that functions as a master regulator of inflammation and bone remodeling. NF-κB activity increases during aging; furthermore, constitutive activation of NF-κB significantly impairs skeletal development in neonatal mice. However, the effects of NF-κB activation using a skeletally mature animal model have not been examined. In the current study, an osteoprogenitor (OP)-specific, doxycycline-regulated NF-κB activated transgenic mouse model (iNF-κB/OP) was generated to investigate the role of NF-κB in bone remodeling in skeletally mature mice. Reduced osteogenesis in the OP-lineage cells isolated from iNF-κB/OP mice was only observed in the absence of doxycycline in vitro. Bone mineral density in the metaphyseal regions of femurs and tibias was reduced in iNF-κB/OP mice. No significant differences in bone volume fraction and cortical bone thickness were observed. Osmium-stained bone marrow fat was increased in epiphyseal and metaphyseal areas in the tibias of iNF-κB/OP mice. These findings suggest that targeting NF-κB activity as a therapeutic strategy may improve bone healing and prevent aging-associated bone loss in aged patients.

Acetabular retroversion in dysplastic hips is associated with decreased 3D femoral head coverage independently from lateral center-edge angle.

INTRODUCTION: The clinical significance of acetabular retroversion in non-dysplastic hips can be explained as pincer-type femoroacetabular impingement (FAI), whereas that in dysplastic hips is not clarified because FAI normally poses little problems for dysplastic hips. We aimed to evaluate three-dimensional (3D) femoral head coverage in dysplastic hips with and without acetabular retroversion and to elucidate the role of acetabular retroversion on the 3D femoral head coverage. MATERIALS AND METHODS: We retrospectively investigated 93 hips in 93 patients (9 males and 84 females) that underwent periacetabular osteotomy for hip dysplasia. Dysplastic hips were divided into anteversion and retroversion groups according to their cranial anteversion, which was measured on the axial section 5 mm caudal to the acetabular roof. The 3D femoral head coverage was provided as a percentage of the acetabulum-covered surface area of the upper femoral hemisphere using a 3D preoperative planning software for total hip arthroplasty. RESULTS: Of the 93 dysplastic hips, 15 hips (16%) were assigned to the retroversion group, which had significantly younger age at surgery (31.9 years versus 39.2 years; p = 0.033). The lateral center-edge angles were comparable between the groups (13.8° versus 12.9°; p = 0.68); however, the hips in the retroversion group had a trend of smaller 3D femoral head coverage than those in the anteversion group (59% versus 63%; p = 0.058). Multivariate analysis using two-way analysis of covariance showed that lateral center-edge angle (partial regression coefficient = 0.83; t value = 17.3; p < 0.001) and acetabular retroversion (partial regression coefficient = - 2.3; t value = - 4.9; p < 0.001) were independent factors that contributed to the 3D femoral head coverage. CONCLUSIONS: Acetabular retroversion in dysplastic hips was associated with decreased 3D femoral head coverage independently from lateral center-edge angle. The age at surgery in the retroversion group was significantly younger, suggesting a relationship between decreased 3D coverage and potentially earlier symptom onset.

Precise immunomodulation of the M1 to M2 macrophage transition enhances mesenchymal stem cell osteogenesis and differs by sex.

OBJECTIVES: Up to 10% of fractures result in undesirable outcomes, for which female sex is a risk factor. Cellular sex differences have been implicated in these different healing processes. Better understanding of the mechanisms underlying bone healing and sex differences in this process is key to improved clinical outcomes. This study utilized a macrophage-mesenchymal stem cell (MSC) coculture system to determine: 1) the precise timing of proinflammatory (M1) to anti-inflammatory (M2) macrophage transition for optimal bone formation; and 2) how such immunomodulation was affected by male versus female cocultures. METHODS: A primary murine macrophage-MSC coculture system was used to demonstrate the optimal transition time from M1 to M2 (polarized from M1 with interleukin (IL)-4) macrophages to maximize matrix mineralization in male and female MSCs. Outcome variables included Alizarin Red staining, alkaline phosphatase (ALP) activity, and osteocalcin protein secretion. RESULTS: We found that 96 hours of M1 phenotype in male cocultures allowed for maximum matrix mineralization versus 72 hours in female cocultures. ALP activity and osteocalcin secretion were also enhanced with the addition of IL-4 later in male versus female groups. The sex of the cells had a statistically significant effect on the optimal IL-4 addition time to maximize osteogenesis. CONCLUSION: These results suggest that: 1) a 72- to 96-hour proinflammatory environment is critical for optimal matrix mineralization; and 2) there are immunological differences in this coculture environment due to sex. Optimizing immunomodulation during fracture healing may enhance and expedite the bone regeneration response. These findings provide insight into precise immunomodulation for enhanced bone healing that is sex-specific.Cite this article: K. Nathan, L. Y. Lu, T. Lin, J. Pajarinen, E. Jämsen, J-F. Huang, M. Romero-Lopez, M. Maruyama, Y. Kohno, Z. Yao, S. B. Goodman. Precise immunomodulation of the M1 to M2 macrophage transition enhances mesenchymal stem cell osteogenesis and differs by sex. Bone Joint Res 2019;8:481-488. DOI: 10.1302/2046-3758.810.BJR-2018-0231.R2.

Optimization and Characterization of Calcium Phosphate Transfection in Mesenchymal Stem Cells.

IMPACT STATEMENT: Mesenchymal stem cells (MSCs) are a promising tool for cell therapy, and gene-modified MSCs further expand their applications. To take full advantage of MSCs as a therapeutic approach, developing effective gene transfer methods is critical. Calcium phosphate transfection is well-established and safe, but the protocols need to be optimized according to different cell types. Currently, there is no optimized protocol for MSCs. This study optimized the protocol of calcium phosphate transfection for MSCs and highlighted the importance of serum during the process of transfection. More interestingly, the behavior of gene overexpression in MSCs in the in vivo environment was verified.

Osteogenic ability of rat bone marrow concentrate is at least as efficacious as mesenchymal stem cells in vitro.

Cell therapy using bone marrow concentrate (BMC) or purified and expanded mesenchymal stem cells (MSCs) has been shown to have a promising osteogenic capacity. However, few studies have directly compared their relative osteogenic ability. The aim of this study was to compare the osteogenic ability of BMC isolated by density gradient centrifugation with bone marrow-derived MSCs in vitro using the cells of 3-month-old Sprague-Dawley rats. The isolated cells were seeded onto 24-well plates (1 × 105 cells/well) and cultured in control growth media, osteogenic media with dexamethasone, or media without dexamethasone (which simulated the in vivo tissue environment). Alkaline phosphatase activity at week 2, osteocalcin using quantitative real-time polymerase chain reaction at week 4, and Alizarin red staining at week 4 were evaluated. In the osteogenic media with dexamethasone, BMC showed equivalent (osteocalcin) or even greater (Alizarin red staining) osteogenic ability compared to MSCs, suggesting that cross-talk among various cells in the BMC leads to greater osteogenesis. Furthermore, in the osteogenic media without dexamethasone, BMC showed equivalent (osteocalcin) or a trend for greater (Alizarin red staining) bone formation than MSCs alone. Our results suggest that BMC has at least comparable bone regeneration potential to MSCs. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B:2500-2506, 2019.

The significance of intraoperative renal pelvic urine and stone cultures for patients at a high risk of post-ureteroscopy systemic inflammatory response syndrome.

We examined the renal pelvic urine culture (RPUC) and stone culture (SC) during ureteroscopy and evaluated their associations with postoperative systemic inflammatory response syndrome (SIRS). We prospectively collected data of 224 patients who underwent ureteroscopic laser lithotripsy from March 2015 to December 2017. We examined the bladder urine culture pre-operatively. If the patients had positive culture results, we treated them with antibiotics for 5-7 days before surgery based on the sensitivity profile. We collected RPUC and SC samples during surgery. After ureteroscopy, patients were closely monitored for any signs of SIRS. Using a logistic regression model, we analyzed how the clinical factors affected the incidence of SIRS. Pre-operative bladder urine culture (PBUC) was positive in 111 patients (49.6%). Intraoperative RPUC was positive in 43 patients (19.2%), and SC was positive in 34 patients (15.2%). Postoperatively, 23 patients (10.3%) were diagnosed with SIRS. A multivariate analysis revealed that female gender, struvite calculi and positive intraoperative RPUC results were significantly associated with postoperative SIRS. Among the 31 patients who were positive for both PBUC and intraoperative RPUC, the pathogens were not consistent in 11 patients (35.5%). Among the 25 patients who were positive for both PBUC and intraoperative SC, the pathogens were not consistent in 13 patients (52.0%). We recommend collecting RPUC and SC samples during ureteroscopy, especially for patients with high risk factors, including female gender, expected struvite calculi and positive PBUC results.

Ghost imaging using a large-scale silicon photonic phased array chip.

We experimentally demonstrate the use of a large-scale silicon-photonic optical phased array (OPA) chip as a compact, low-cost, and potentially high-speed light illuminating device for ghost imaging (GI) applications. By driving 128 phase shifters of a newly developed silicon OPA chip using rapidly changing random electrical signals, we successfully retrieve a slit pattern with over 90 resolvable points in one dimension. We then demonstrate 2D imaging capability by sweeping the wavelength. With the potential of integrating high-speed phase modulators, tunable lasers, grating couplers, and CMOS driver circuit on the same silicon platform, this work paves the way towards realizing ultrahigh-speed and low-cost single-chip GI devices.

Preconditioned or IL4-Secreting Mesenchymal Stem Cells Enhanced Osteogenesis at Different Stages.

IMPACT STATEMENT: Pathogen-associated molecular patterns, damage-associated molecular patterns, and other noxious stimuli activate macrophages to induce the proinflammatory responses. Modulation of inflammatory macrophages (M1) into an anti-inflammatory tissue repair macrophage (M2) phenotype at the appropriate time optimizes bone remodeling and regeneration. Simulating the proinflammatory stimuli by using preconditioned mesenchymal stem cells (MSCs) at an earlier stage, and alleviate the inflammation by using IL4-secreting MSCs at a later stage could further optimize bone regeneration in chronic inflammatory conditions, including periprosthetic osteolysis.

Trained murine mesenchymal stem cells have anti-inflammatory effect on macrophages, but defective regulation on T-cell proliferation.

Mesenchymal stem cell (MSC)-mediated immunomodulation affects both innate and adaptive immune systems. These responses to environmental cues, such as pathogen-associated molecular patterns, damage-associated molecular patterns, or proinflammatory cytokines, are crucial for resolution of inflammation, as well as successful tissue healing and regeneration. We observed that intermittent, repeated exposure of MSCs to LPS induced stronger NF-κB activation than singular stimulation. A similar phenomenon, named innate immune memory or trained immunity, has been reported with macrophages. However, the potential regulation of "immune memory" in nonclassic immune cells, such as MSCs, has not been reported. In the current study, we chose IFN-γ plus TNF-α restimulation-induced iNOS expression as a model of MSC activation, because IFN-γ and TNF-α play crucial roles in MSC-mediated immunomodulation. The iNOS expression was enhanced in LPS-trained MSCs, 3 d after a washout period following primary stimulation. LPS-trained MSCs enhanced the anti-inflammatory (arginase 1 and CD206) marker expression, but decreased the proinflammatory marker (TNF-α, IL-1ß, iNOS, and IL-6) expression using an MSC-macrophage coculture model. In contrast, LPS-trained MSCs demonstrated a defective regulation on CD4 T-cell proliferation. Mechanistic studies suggested that histone methylation and the JNK pathway are involved in LPS-trained immunomodulation in MSCs. Our results demonstrate differential immunomodulatory effects of trained MSCs on macrophages and T cells. These immunomodulatory consequences are critical, because they will have a major impact on current MSC-based cell therapies.-Lin, T., Pajarinen, J., Kohno, Y., Huang, J.-F., Maruyama, M., Romero-Lopez, M., Nathan, K., Yao, Z., Goodman, S. B. Trained murine mesenchymal stem cells have anti-inflammatory effect on macrophages, but defective regulation on T-cell proliferation.