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Cellular senescence is associated with osteonecrosis of the femoral head while mesenchymal stem cell conditioned medium inhibits bone collapse.

ABSTRACT: Osteonecrosis of the femoral head (ONFH) is a type of ischemic osteonecrosis that causes pain, loss of function, and femoral head collapse. Here, we analyzed samples of femoral heads excised from patients with ONFH to clarify the relationship between ischemic osteonecrosis and cellular senescence. X-gal staining was strong and p16INK4a-positive cells were abundant in the transitional region of ONFH. The β-galactosidase-positive cells in the transitional region were also positive for nestin, periostin, or DMP-1. In contrast, no β-galactosidase-positive cells were detected in the healthy region. The senescence-associated p16INK4a, p21, and p53 were upregulated in ONFH tissue. We also examined and analyzed a mouse ischemic femoral osteonecrosis model in vivo to verify the association between ONFH and cellular senescence. Human mesenchymal stem cell-conditioned medium (MSC-CM) was administered to determine its therapeutic efficacy against cellular senescence and bone collapse. MSC-CM reduced the number of senescent cells and downregulated the aforementioned senescence-related genes. It also decreased the number of empty lacunae 4 weeks after ischemia induction and promoted bone formation. At 6 weeks post-surgery, MSC-CM increased the trabecular bone volume, thereby suppressing bone collapse. We conclude that cellular senescence is associated with ONFH and that MSC-CM suppresses bone collapse in this disorder.

SUBMITTER: Okamoto M

PROVIDER: S-EPMC10858285 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Cellular senescence is associated with osteonecrosis of the femoral head while mesenchymal stem cell conditioned medium inhibits bone collapse.

Okamoto Masanori M Nakashima Hiroaki H Sakai Kiyoshi K Takegami Yasuhiko Y Osawa Yusuke Y Watanabe Junna J Ito Sadayuki S Hibi Hideharu H Imagama Shiro S

Scientific reports 20240209 1

Osteonecrosis of the femoral head (ONFH) is a type of ischemic osteonecrosis that causes pain, loss of function, and femoral head collapse. Here, we analyzed samples of femoral heads excised from patients with ONFH to clarify the relationship between ischemic osteonecrosis and cellular senescence. X-gal staining was strong and p16INK4a-positive cells were abundant in the transitional region of ONFH. The β-galactosidase-positive cells in the transitional region were also positive for nestin, peri ...[more]

PMID: 38337011

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Project description:BackgroundRadiation ulcers are a common and severe injury after uncontrolled exposure to ionizing radiation. The most important feature of radiation ulcers is progressive ulceration, which results in the expansion of radiation injury to the nonirradiated area and refractory wounds. Current theories cannot explain the progression of radiation ulcers. Cellular senescence refers to as irreversible growth arrest that occurs after exposure to stress, which contributes to tissue dysfunction by inducing paracrine senescence, stem cell dysfunction and chronic inflammation. However, it is not yet clear how cellular senescence facilitates the continuous progression of radiation ulcers. Here, we aim to investigate the role of cellular senescence in promoting progressive radiation ulcers and indicate a potential therapeutic strategy for radiation ulcers.MethodsRadiation ulcer animal models were established by local exposure to 40 Gy X-ray radiation and continuously evaluated for >260 days. The roles of cellular senescence in the progression of radiation ulcers were assessed using pathological analysis, molecular detection and RNA sequencing. Then, the therapeutic effects of conditioned medium from human umbilical cord mesenchymal stem cells (uMSC-CM) were investigated in radiation ulcer models.ResultsRadiation ulcer animal models with features of clinical patients were established to investigate the primary mechanisms responsible for the progression of radiation ulcers. We have characterized cellular senescence as being closely associated with the progression of radiation ulcers and found that exogenous transplantation of senescent cells significantly aggravated them. Mechanistic studies and RNA sequencing suggested that radiation-induced senescent cell secretions were responsible for facilitating paracrine senescence and promoting the progression of radiation ulcers. Finally, we found that uMSC-CM was effective in mitigating the progression of radiation ulcers by inhibiting cellular senescence.ConclusionsOur findings not only characterize the roles of cellular senescence in the progression of radiation ulcers but also indicate the therapeutic potential of senescent cells in their treatment.

Project description:Femoral head collapse is a key reference point for determining a treatment regimen of femoral head osteonecrosis. However, there are no effective preventive measures and the efficacy of hip-preserving surgery is unsatisfactory due to the unclear mechanism of collapse. This study aimed to identify and validate miRNAs differentially expressed in collapse and non-collapse areas of the osteonecrotic femoral head, and to predict the target genes and pathways of these miRNAs.Nine samples passed the quality control test. A total of 2085 differentially expressed miRNAs were detected, among which 433 miRNAs showed differential expression in the T1 group compared to the W1 group; 344 miRNAs showed differential expression in the T2 group compared to the W2 group; 107 miRNAs showed differential expression in the T3 group compared to the W3 group. After combining data from all three patients, 10 miRNAs showed differential expression in the collapse area (T1+T2+T3) compared to the non-collapse area (W1+W2+W3). Compared to the normal area, has-miR-195-5p showed the most significant downregulation. Expression results from RT-PCR revealed that the expression of hsa-miR-195-5p in the collapse area (T1+T2+T3) was significantly lower than that in the non-collapse area (W1+W2+W3) and normal area (Z1+Z2+Z3). 157 genes were perdicted as the target gene of hsa-miR-195-5p.Femoral heads of three patients (2 males and 1 female) treated by total hip arthroplasty surgery for steroid-induced femoral head osteonecrosis were selected based on inclusion and exclusion criteria. Bone tissue samples were obtained from the collapse area (T), non-collapse area (W), and normal area (Z) according to the anatomical structure of osteonecrotic femoral heads. Total RNA was extracted from the samples and the microarray chip was scanned. miRNAs showing differential expressions of more than 1.5-fold were selected and was validated by RT-PCR. TargetScan, mirBase and miRanda bioinformatics software was used to predict target genes and identify possible pathways involving these genes.miR-195-5p showed the most significant difference in the collapse area of osteonecrotic femoral heads, suggesting that collapse may be related to the downregulation of miR-195-5p.

Project description:BackgroundFemoral head collapse is a critical pathological change and is regarded as turning point in disease progression in osteonecrosis of the femoral head (ONFH). In this study, we aim to build an automatic femoral head collapse prediction pipeline for ONFH based on magnetic resonance imaging (MRI) radiomics.MethodsIn the segmentation model development dataset, T1-weighted MRI of 222 hips from two hospitals were retrospectively collected and randomly split into training (n = 190) and test (n = 32) sets. In the prognosis prediction model development dataset, 206 hips were also retrospectively collected from two hospitals and divided into training set (n = 155) and external test set (n = 51) according to data source. A deep learning model for automatic lesion segmentation was trained with nnU-Net, from which three-dimensional regions of interest were segmented and a total of 107 radiomics features were extracted. After intra-class correlation coefficients screening, feature correlation coefficient screening and Least Absolute Shrinkage and Selection Operator regression feature selection, a machine learning model for ONFH prognosis prediction was trained with Logistic Regression (LR) and Light Gradient Boosting Machine (LightGBM) algorithm.ResultsThe segmentation model achieved an average dice similarity coefficient of 0.848 and an average 95% Hausdorff distance of 3.794 in the test set, compared to the manual segmentation results. After feature selection, nine radiomics features were included in the prognosis prediction model. External test showed that the LightGBM model exhibited acceptable predictive performance. The area under the curve (AUC) of the prediction model was 0.851 (95% CI: 0.7268-0.9752), with an accuracy of 0.765, sensitivity of 0.833, and specificity of 0.727. Decision curve analysis showed that the LightGBM model exhibited favorable clinical utility.ConclusionThis study presents an automated pipeline for predicting femoral head collapse in ONFH with acceptable performance. Further research is necessary to determine the clinical applicability of this radiomics-based approach and to assess its potential to assist in treatment decision-making for ONFH.

Project description:PurposeThe objective of this study was to identify potential genes implicated in the "peri-collapse" synovium of osteonecrosis of the femoral head through coding gene sequencing and to further clarify their specific mechanisms via in vitro experiments.MethodsSteroid-induced osteonecrosis of the femoral head (SIONFH) (n = 3), femoral neck fracture (FNF) (n = 3), and hip osteoarthritis (HOA) (n = 3) Synovial tissue of the hip joint was collected in total hip arthroplasty. A cellular model of SIONFH constructed from rat synovial fibroblasts by lipopolysaccharide intervention. Lentiviral technology was used to construct a model for fibroblast knockout of the Irf7 gene. HE was used to compare the characteristics of synovial tissue damage, and immunofluorescence and immunohistochemistry were used to compare the expression levels of VIM, IRF7, and IFNα. PCR, WB, and IF were used to examine Irf7 knockdown efficiency, chondrocyte proliferation (Col2a1, Aggrecan, Sox9), cartilage matrix degradation (Mmp13), and apoptosis (Bcl2, Bax, and Caspase3) expression under co-culture conditions. Crystalline violet staining was used to observe the migration rate of fibroblasts, and flow cytometry was used to detect the apoptosis level of chondrocytes under co-culture conditions.ResultsTranscriptome sequencing of synovial tissue and fibroblasts ultimately screened for six differential genes, HOOK1, RNPC3, KCNA3, CD48, IRF7, SAMD9. Compared to FNF and HOA, synovial inflammatory cell recruitment and synovial hyperplasia were more pronounced in SIONFH. IF and IHC confirmed high expression of IRF7 and IFNα in the synovium of SIONFH. PCR and WB results suggested that fibroblasts highly expressed Irf7, Hook1, Rnpc3, Kcna3, Cd48, Samd9, Il-6, and Tnfα after lipopolysaccharide intervention, and the expression levels of Il-6 and Tnfα were significantly reduced after knockdown of Irf7 (P < 0.001). In the co-culture system, fibroblasts intervened with lipopolysaccharide significantly promoted chondrocyte apoptosis, the rate of cartilage matrix degradation, while inhibiting the level of chondrocyte proliferation, and this result was significantly reversed in Irf7 knockout fibroblasts. This was supported by flow cytometry results.ConclusionsIRF7, HOOK1, RNPC3, KCNA3, CD48, and SAMD9 as potential genes affecting the progression of SIONFH collapse. Irf7 mediates the fibroblast inflammatory response and affects the collapse process of SIONFH by influencing chondrocyte apoptosis. Thus, intervention in IRF7 holds promise as one of the key targets for reversing the collapse process of SIONFH.

Project description:BackgroudOutcomes of traditional treatment for osteonecrosis of the femoral head (ONFH) are not always satisfactory. Hence, cell-supplementation therapy has been attempted to facilitate necrotic-tissue regeneration. Adipose-derived mesenchymal stem cell (ADMSC) transplantation is potentially advantageous over bone marrow-derived MSC implantation, but its outcomes for ONFH remain unclear. The aim of this study was to determine 2-year radiological and clinical outcomes of culture-expanded autologous ADMSC implantation for ONFH.MethodsEighteen hips with necrotic lesions involving ≥ 30% of the femoral head were included. ADMSCs were harvested by liposuction and culture expanded for 3 passages over 3 weeks. With a 6-mm single drilling, ADMSCs were implanted into the necrotic zone. All patients underwent magnetic resonance imaging (MRI), single-photon emission computed tomography/computed tomography (SPECT/CT) at screening and 6 months, 12 months, and 24 months postoperatively. The primary outcome was the change in the size of necrotic area on MRI. Secondary outcomes were changes in clinical scores and radioisotope uptake on SPECT/CT. Conversion total hip arthroplasty (THA) was defined as the endpoint.ResultsPreoperatively, the necrotic lesion extent was 63.0% (38.4%-96.7%) of the femoral head. The mean Harris hip score was 89.2, the University of California at Los Angeles (UCLA) score was 5.6, and Western Ontario and McMaster Universities Arthritis index (WOMAC) was 79.4. Three patients underwent THA and 1 patient died in an accident. Finally, 11 patients (14 hips) were available for ≥ 2-year follow-up. At the last follow-up, no surgery-related complications occurred, and 14 of 17 hips (82%) were able to perform daily activities without THA requirement. There was no significant decrease in lesion size between any 2 intervals on MRI. However, widening of high signal intensity bands on T2-weighted images inside the necrotic lesion was observed in 9 of 14 hips (64%); 11 of 14 hips (79%) showed increased vascularity on SPECT/CT at 2 years postoperatively. No significant differences were observed between preoperative and 24-month mean Harris hip score (89.2 vs. 88.6), WOMAC (79.4 vs. 75.7), and UCLA score (5.6 vs. 6.2).ConclusionsOur outcomes suggest that culture-expanded ADMSC implantation is a viable option for ONFH treatment without adverse events.

Dataset Information

Cellular senescence is associated with osteonecrosis of the femoral head while mesenchymal stem cell conditioned medium inhibits bone collapse.

Publications

Cellular senescence is associated with osteonecrosis of the femoral head while mesenchymal stem cell conditioned medium inhibits bone collapse.

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