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Changed cellular functions and aberrantly expressed miRNAs and circRNAs in bone marrow stem cells in osteonecrosis of the femoral head.

ABSTRACT: The present study aimed to detect the correlations between altered cellular functions in bone marrow stem cells (BMSCs) and osteonecrosis of the femoral head (ONFH). By profiling the aberrant expression of miRNAs and circRNAs in BMSCs isolated from ONFH patients, the present study aimed to further explore the potential regulatory mechanisms of action of circRNAs in ONFH using integrated bioinformatics analysis. BMSCs were isolated from seven ONFH patients and seven controls. Cellular functions, including proliferation, apoptosis and differentiation, were compared. miRNA and circRNA sequencing were conducted using RNA samples of three ONFH patients and three controls to identify differentially expressed circRNAs and miRNAs. The expression of hsa_circ_0000219, hsa_circ_0004588 and hsa_circ_0005936 were validated by qPCR. Target miRNAs were also predicted and validated by qPCR and circRNA?miRNA co?expression networks were constructed. BMSCs of ONFH patients displayed decreased proliferation and increased apoptosis during in vitro culturing. In addition, reduced osteogenesis and enhanced adipogenesis were found in the ONFH group. A total of 129 miRNAs and 231 circRNAs were detected to be differentially expressed. The expression levels of hsa_circ_0000219, hsa_circ_0004588 and hsa_circ_0005936 were significantly decreased in BMSCs of ONFH patients. A number of target miRNAs related to cell proliferation, apoptosis and differentiation were predicted for hsa_circ_0000219 and hsa_circ_0005936. The expression levels of miR?144?3p and miR?1270 were found to be elevated in ONFH patients, which was consistent with miRNA sequencing data and competitive endogenous RNA hypothesis. Time?dependent expression patterns of hsa_circ_0000219, hsa_circ_0004588, hsa_circ_0005936, miR?144?3p and miR?1270 were also validated during osteogenic and adipogenic differentiation in BMSCs. The results of the present study substantiated the involvement of BMSCs in ONFH development. hsa_circ_0000219 and hsa_circ_0005936 may regulate the progression of ONFH by mediating the proliferation and differentiation of BMSCs by sponging miRNAs.

SUBMITTER: Xiang S

PROVIDER: S-EPMC7015133 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Changed cellular functions and aberrantly expressed miRNAs and circRNAs in bone marrow stem cells in osteonecrosis of the femoral head.

Xiang Shuai S Li Zeng Z Weng Xisheng X

International journal of molecular medicine 20200108 3

The present study aimed to detect the correlations between altered cellular functions in bone marrow stem cells (BMSCs) and osteonecrosis of the femoral head (ONFH). By profiling the aberrant expression of miRNAs and circRNAs in BMSCs isolated from ONFH patients, the present study aimed to further explore the potential regulatory mechanisms of action of circRNAs in ONFH using integrated bioinformatics analysis. BMSCs were isolated from seven ONFH patients and seven controls. Cellular functions, ...[more]

PMID: 31922208

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Project description:BackgroundGlucocorticoid usage and alcohol abuse are the most widely accepted risk factors for nontraumatic osteonecrosis of femoral head (ONFH). Despite distinct etiologies between glucocorticoid-associated ONFH (GONFH) and alcohol-associated ONFH (AONFH), little is known about the differences of the microarchitectural and histomorphologic characteristics between these subtypes of ONFH.PurposesTo investigate bone microarchitecture, bone remodeling activity and histomorphology characteristics of different regions in femoral heads between GONFH and AONFH.MethodsFrom September 2015 to October 2020, 85 patients diagnosed with GONFH and AONFH were recruited. Femoral heads were obtained after total hip replacement. Femoral head specimens were obtained from 42 patients (50 hips) with GONFH and 43 patients (50 hips) with AONFH. Micro-CT was utilized to assess the microstructure of 9 regions of interest (ROIs) in the femoral head. Along the supero-inferior orientation, the femoral head was divided into necrotic region, reactive interface, and normal region; along the medio-lateral orientation, the femoral head was divided into medial region, central region and lateral region. Decalcified and undecalcified bone histology was subsequently performed to evaluate histopathological alterations and bone remodeling levels.ResultsIn the necrotic region, most of the microarchitectural parameters did not differ significantly between GONFH and AONFH, whereas both the reactive interface and normal region revealed a less sclerotic microarchitecture but a higher bone remodeling level in GONFH than AONFH. Despite similar necrotic pathological manifestations, subchondral trabecular microfracture in the necrotic region was more severe and vasculature of the reactive interface was more abundant in GONFH.ConclusionsGONFH and AONFH shared similar microarchitecture and histopathological features in the necrotic region, while GONFH exhibited a less sclerotic microarchitecture and a more active bone metabolic status in both the reactive interface and normal region. These differences between GONFH and AONFH in bone microarchitectural and histopathological characteristics might contribute to the development of disease-modifying prevention strategies and treatments for ONFH, taking into etiologies.

Project description:ObjectiveBone marrow-derived mesenchymal stem cells (BMSCs) have multilineage differentiation potential, which allows them to progress to osteogenesis, adipogenesis, and chondrogenesis. An imbalance of differentiation between osteogenesis and adipogenesis will result in pathologic conditions inside the bone. This type of imbalance is also one of the pathological findings in osteonecrosis of the femoral head (ONFH). Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) was previously reported to mediate the differentiation of mesenchymal stem cells. This study investigated the expression of the osteogenesis regulator Runx2, osteocalcin, the adipogenesis regulator PPARγ, and COUP-TFII in the femoral head tissue harvested from ONFH patients, and characterized the effect of COUP-TFII on the differentiation of primary BMSCs.MethodsThirty patients with ONFH were recruited and separated into 3 groups: the trauma-, steroid- and alcohol-induced ONFH groups (10 patients each). Bone specimens were harvested from patients who underwent hip arthroplasty, and another 10 specimens were harvested from femoral neck fracture patients as the control group. Expression of the osteogenesis regulator Runx2, osteocalcin, the adipogenesis regulator PPARγ, C/EBP-α, and COUP-TFII was analyzed by Western blotting. Primary bone marrow mesenchymal cells were harvested from ONFH cells treated with COUP-TFII RNA interference to evaluate the effect of COUP-TFII on MSCs.ResultsONFH patients had significantly increased expression of the adipogenesis regulator PPARγ and C/EBP-α and decreased expression of the osteogenesis regulator osteocalcin. ONFH bone tissue also revealed higher COUP-TFII expression. Immunohistochemical staining displayed strong COUP-TFII immunoreactivity adjacent to osteonecrotic trabecular bone. Increased COUP-TFII expression in the bone tissue correlated with increased PPARγ and decreased osteocalcin expression. Knockdown of COUP-TFII with siRNA in BMSCs reduced adipogenesis and increased osteogenesis in mesenchymal cells.ConclusionIncreased COUP-TFII expression mediates the imbalance of BMSC differentiation and progression to ONFH in patients. This study might reveal a new target in the treatment of ONFH.

Dataset Information

Changed cellular functions and aberrantly expressed miRNAs and circRNAs in bone marrow stem cells in osteonecrosis of the femoral head.

Publications

Changed cellular functions and aberrantly expressed miRNAs and circRNAs in bone marrow stem cells in osteonecrosis of the femoral head.

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