The objective of this study was to evaluate the extent of stromal cell-derived factor-1's (SD... more The objective of this study was to evaluate the extent of stromal cell-derived factor-1's (SDF-1) involvement in the pathogenesis of idiopathic versus post-traumatic OA by comparing differences in synovial membrane morphology, SDF-1 synovial fluid (SF) concentrations, and matrix metalloproteinase-13 (MMP-13) SF concentrations. Thirty-six 3-month-old Hartley guinea pigs were obtained and divided into 6 groups. Upon sacrifice, India Ink staining was used to evaluate gross morphology, Safranin O/Fast green staining was used to assess cartilage damage, H/E staining was employed to visualize the synovium, and SF samples were obtained for biochemical analyses. Sandwich ELISA was used to quantify the SF concentrations of SDF-1 and MMP-13. 12 month-old, idiopathic OA guinea pigs and 5.5 month-old ACLT animals had comparable cartilage damage when evaluated by the Modified Mankin Score. SDF-1 and MMP-13 concentrations were not statistically different between the two groups. The synovial m...
The cytoskeleton network is believed to play an important role in the biomechanical properties of... more The cytoskeleton network is believed to play an important role in the biomechanical properties of the chondrocyte. Ours and other laboratories have demonstrated that chondrocytes exhibit a viscoelastic solid creep behavior in vitro and that viscoelastic properties decrease in osteoarthritic chondrocytes. In this study, we aimed to understand whether the alteration of viscoelastic properties is associated with changes in cytoskeleton components of ageing chondrocytes from rabbit knee articular cartilage. Three age groups were used for this study: young (2-months-old, N=23), adult (8-months-old, N=23), and old (31-months-old, N=23) rabbit groups. Cartilage structure and proteoglycan and type II collagen content were determined by H&E and Toluidine Blue staining, and type II collagen antibody. The detailed structure of the chondrocytes in all groups was visualized using transmission electron microscopy (TEM). Chondrocytes were isolated from full-thickness knee cartilage of rabbits from...
We have recently reported that ROCK1 deficiency in mouse embryonic fibroblasts (MEF) has superior... more We have recently reported that ROCK1 deficiency in mouse embryonic fibroblasts (MEF) has superior anti-apoptotic and pro-survival effects than antioxidants against doxorubicin, a chemotherapeutic drug. Although oxidative stress is the most widely accepted mechanism, our studies suggest that ROCK1-dependent actin cytoskeleton remodeling plays a more important role in mediating doxorubicin cytotoxicity on MEFs. To further explore the contributions of ROCK1-dependent actin cytoskeleton remodeling in response to stress, this study investigates the mechanistic differences between the cytotoxic effects of doxorubicin versus hydrogen peroxide (H2O2), with a focus on cytoskeleton alterations, apoptosis and necrosis induction. We found that both types of stress induce caspase activation but with different temporal patterns and magnitudes in MEFs: H2O2 induces the maximal levels (2 to 4-fold) of activation of caspases 3, 8, and 9 within 4 h, while doxorubicin induces much higher maximal levels (15 to 25-fold) of caspases activation at later time points (16-24 h). In addition, necrosis induced by H2O2 reaches maximal levels within 4 h while doxorubicin-induced necrosis largely occurs at 16-24 h secondary to apoptosis. Moreover, both types of stress induce actin cytoskeleton remodeling but with different characteristics: H2O2 induces disruption of stress fibers associated with cytosolic translocation of phosphorylated myosin light chain (p-MLC) from stress fibers, while doxorubicin induces cortical F-actin formation associated with cortical translocation of p-MLC from central stress fibers. Furthermore, N-acetylcysteine (an antioxidant) is a potent suppressor for H2O2-induced cytotoxic effects including caspase activation, necrosis, and cell detachment, but shows a much reduced inhibition on doxorubicin-induced changes. On the other hand, ROCK1 deficiency is a more potent suppressor for the cytotoxic effects induced by doxorubicin than by H2O2. These results support the notion that doxorubicin induces caspase activation, necrosis, and actin cytoskeleton alterations largely through ROCK1-dependent and oxidative stress-independent pathways.
Frontiers of Energy and Power Engineering in China, 2009
For grain in-store drying, a solar assisted drying process has been developed, which consists of ... more For grain in-store drying, a solar assisted drying process has been developed, which consists of a set including a solar-assisted heat pump, a ventilation system, a grain stirrer, etc. In this way, low power consumption, short cycle time and water content uniformity can be achieved in comparison with the conventional method. A solar-assisted heat pump drying system has been designed
Human urine-derived stem cells (hUSCs) are a newly found type of stem cell with a potential for t... more Human urine-derived stem cells (hUSCs) are a newly found type of stem cell with a potential for therapeutic application in urology. The aim of this study is to investigate whether hUSCs contribute to cartilage regeneration. Despite their characterization with multi-lineage differentiation capacities, in terms of osteogenesis, adipogenesis and myogenesis, hUSCs do not show the ability to differentiate into chondrocytes. Human bone marrow stromal cells (hBMSCs) are a tissue-specific stem cell for endochondral bone formation; however, repeated-passage hBMSCs have a lower capacity for chondrogenic differentiation. We found that the extracellular matrix (ECM) deposited by hUSCs (UECM) can greatly recharge repeated-passage hBMSCs toward chondrogenic differentiation, a result that might be explained by trophic factors released from hUSCs being immobilized in UECM. We also found that ECM from repeated-passage hBMSCs (BECM) have a limited rejuvenation effect. The Wnt11-mediated noncanonical ...
Chondrosarcoma is the most common primary malignant bone tumor in adults, has no effective system... more Chondrosarcoma is the most common primary malignant bone tumor in adults, has no effective systemic treatment, and patients with this disease have poor survival. Altered expression of microRNA (miR) is involved in tumorigenesis, however its role in chondrosarcoma is undetermined. MicroRNA-181a is overexpressed in high grade chondrosarcoma, is upregulated by hypoxia, and increases VEGF expression. Here, the purpose was to determine the mechanism of miR-181a regulation of VEGF, determine if miR-181a overexpression promotes tumor progression, and to evaluate an antagomir-based approach for chondrosarcoma treatment. Therapeutic inhibition of miR-181a decreased expression of VEGF and MMP1 in vitro, and angiogenesis, MMP1 activity, tumor growth, and lung metastasis, all by more than 50%, in a xenograft mouse model. A target of miR-181a is regulator of G-protein signaling 16 (RGS16), a negative regulator of CXC chemokine receptor 4 (CXCR4) signaling. CXCR4 signaling is increased in chondro...
Alterations of genes encoding transcriptional regulators of lymphoid development are a hallmark o... more Alterations of genes encoding transcriptional regulators of lymphoid development are a hallmark of B-progenitor acute lymphoblastic leukemia (B-ALL), and most commonly involve PAX5, encoding the DNA-binding transcription factor paired-box 5. The majority of PAX5 alterations in ALL are heterozygous, and key PAX5 target genes are expressed in leukemic cells, suggesting that PAX5 may be a haploinsufficient tumor suppressor. To examine the role of PAX5 alterations in leukemogenesis, we performed mutagenesis screens of mice heterozygous for a loss-of-function Pax5 allele. Both chemical and retroviral mutagenesis resulted in a significantly increased penetrance and reduced latency of leukemia, with a shift to B-lymphoid lineage. Genomic profiling identified a high frequency of secondary genomic mutations, deletions and retroviral insertions targeting B-lymphoid development, including Pax5, and additional genes and pathways mutated in ALL, including tumor suppressors, Ras and JAK-STAT sign...
The Hedgehog (Hh) family of proteins consists of Indian hedgehog (Ihh), sonic hedgehog (Shh), and... more The Hedgehog (Hh) family of proteins consists of Indian hedgehog (Ihh), sonic hedgehog (Shh), and desert hedgehog (Dhh). These proteins serve as essential regulators in a variety of developmental events. Ihh is mainly produced and secreted by prehypertrophic chondrocytes and regulates chondrocyte hypertrophy and endochondral bone formation during growth plate development. Tissue-specific deletion of the Ihh gene (targeted by Col2a1-Cre) causes early lethality in mice. Transgenic mice with induced Ihh expression exhibit increased chondrocyte hypertrophy and cartilage damage resembling human osteoarthritis (OA). During OA development, chondrocytes recapitulate the differentiation process that happens during the fetal status and which does not occur to an appreciable degree in adult articular cartilage. Ihh expression is up-regulated in human OA cartilage, and this upregulation correlates with OA progression and changes in chondrocyte morphology. A genetic study in mice further showed ...
Ouabain is a common tool to explore the pathophysiological changes in adult mammalian cochlea in ... more Ouabain is a common tool to explore the pathophysiological changes in adult mammalian cochlea in vivo. In prior studies, locally administering ouabain via round window membrane demonstrated that the ototoxic effects of ouabain in vivo varied among mammalian species. Little is known about the ototoxic effects in vitro. Thus, we prepared cochlear organotypic cultures from postnatal day-3 rats and treated these cultures with ouabain at 50, 500, and 1000 μM for different time to elucidate the ototoxic effects of ouabain in vitro and to provide insights that could explain the comparative ototoxic effects of ouabain in vivo. Degeneration of cochlear hair cells and spiral ganglion neurons was evaluated by hair-cell staining and neurofilament labeling, respectively. Annexin V staining was used to detect apoptotic cells. A quantitative RT-PCR apoptosis-focused gene array determined changes in apoptosis-related genes. The results showed that ouabain-induced damage in vitro was dose and time d...
Osteoarthritis (OA) is closely associated with aging, but its underlying mechanism is unclear. Re... more Osteoarthritis (OA) is closely associated with aging, but its underlying mechanism is unclear. Recent publications were reviewed to elucidate the connection between aging and OA. With increasing OA incidence, more senior people are facing heavy financial and social burdens. Age-related OA pathogenesis is not well understood. Recently, it has been realized that age-related changes in other tissues besides articular cartilage may also contribute to OA development. Many factors including senescence-related secretory phenotypes, chondrocytes' low reactivity to growth factors, mitochondrial dysfunction and oxidative stress, and abnormal accumulation of advanced glycation end products (AGEs) may all play key roles in the pathogenesis of age-related OA. Lately, epigenetic regulation of gene expression was recognized for its impact on age-related OA pathogenesis. Up to now, few studies have been reported about the role of miRNA and long-noncoding RNA (lncRNA) in age-related OA. Research...
Genetically engineered mouse models (GEMMs) of human cancer are important for advancing our under... more Genetically engineered mouse models (GEMMs) of human cancer are important for advancing our understanding of tumor initiation and progression as well as for testing novel therapeutics. Retinoblastoma is a childhood cancer of the developing retina that initiates with biallelic inactivation of the RB1 gene. GEMMs faithfully recapitulate the histopathology, molecular, cellular, morphometric, neuroanatomical and neurochemical features of human retinoblastoma. In this study, we analyzed the genomic and epigenomic landscape of murine retinoblastoma and compared them to human retinoblastomas to gain insight into shared mechanisms of tumor progression across species. Similar to human retinoblastoma, mouse tumors have low rates of single nucleotide variations. However, mouse retinoblastomas have higher rates of aneuploidy and regional and focal copy number changes that vary depending on the genetic lesions that initiate tumorigenesis in the developing murine retina. Furthermore, the epigenet...
Zhonghua wai ke za zhi [Chinese journal of surgery], Jan 15, 2007
To investigate the properties of screw-bone interface of expansive pedicle screw (EPS) in osteopo... more To investigate the properties of screw-bone interface of expansive pedicle screw (EPS) in osteoporotic sheep using micro-CT and histology. Six female sheep with bilateral ovariectomy-induced osteoporosis were employed in this experiment and were randomly assigned into 2 groups: A and B. After EPS insertion in each femoral condyles, sheep in group A were bred for 3 months, while those in group B 6 months. Femoral condyles with EPS were 3D-imaged and reconstructed by micro-CT. Histology was evaluated thereafter. The trabecular microstructure was denser at the screw-bone interface than in the distant parts in expansive section, especially within spiral marking. In the non-expansive section, however, there was no significant difference between the interface and the distant parts. The regions of interest (ROI) adjacent to EPS were reconstructed and analyzed by micro-CT using the same thresholds. The 3D-parameters generated, including tissue mineral density (TMD), bone volume fraction (BV...
One of the hallmarks of osteoarthritic cartilage is the loss of chondrocyte cellularity due to ce... more One of the hallmarks of osteoarthritic cartilage is the loss of chondrocyte cellularity due to cell death. However, considerable controversy has recently arisen surrounding the extent of apoptotic cell death involved in development of osteoarthritis (OA). To shed light on this issue, we characterized cell death in primary OA chondrocytes mediated by the CD95 (Fas) pathway. Treatment of chondrocytes with anti-CD95 not only increased the rate of cell death but also increased the production of CD95 ligand by chondrocytes. This reveals a novel autocrine regulatory loop whereby activated chondrocytes may amplify CD95 signals by inducing synthesis of CD95 ligand. Multiple morphologic detection analyses indicated that apoptosis accounted for only a portion of chondrocyte death, whereas the other chondrocytes died by necrosis. Both chondrocyte apoptosis and necrosis depended on the activity of p38 mitogen-activated protein kinase (MAPK) within chondrocytes. Treatment of chondrocytes with th...
Histone deacetylase 4 (HDAC4) is a critical negative regulator for chondrocyte hypertrophy by bin... more Histone deacetylase 4 (HDAC4) is a critical negative regulator for chondrocyte hypertrophy by binding to and inhibiting Runx2, a critical transcription factor for chondrocyte hypertrophy. It is unclear how HDAC4 expression and stability are regulated during growth plate development. We report here that inhibition of mitogen-activated protein kinase (MAPK) p38 by dominant negative p38 or p38 inhibitor prevents HDAC4 degradation. Mutation of a potential caspase-2 and 3 cleavage site Asp289 stabilizes HDAC4 in chondrocytes. In contrast, constitutively active MAPK kinase 6 (constitutive activator of p38) transgenic mice exhibit decreased HDAC4 content in vivo. We also observed that p38 stimulates caspase-3 activity in chondrocytes. Inhibition of p38 or caspases reduced HDAC4 degradation. HDAC4 inhibited Runx2 promoter activity in a dose-dependent manner and caspase inhibitors further enhanced this inhibition by preventing HDAC4 degradation. Overall, these results demonstrate that p38 pr...
It had been found that the concentration of chemokine stromal cell-derived factor-1 (SDF-1) was s... more It had been found that the concentration of chemokine stromal cell-derived factor-1 (SDF-1) was significantly higher in synovial fluid (SF) of patients with osteoarthritis (OA; > or = 200 ng/ml) and rheumatoid arthritis (RA; > or = 700 ng/ml) compared to controls (< or = 100 ng/ml). Our aim was to determine whether the pathological concentration of SDF-1 induces chondrocyte death and to investigate mechanisms underlying such death. Human OA chondrocytes were treated with different doses of SDF-1, or in combination with SF from patients with arthritis. Apoptotic and necrotic cells were labeled by annexin V and propidium iodide, respectively, and quantified by FACS analysis. Caspase-3 activity was quantified by a plate absorbance assay, and matrix metalloproteinase 13 mRNA levels were determined by RT-PCR. The release of high mobility group box chromatin protein 1, a specific marker of cell necrosis, and the activities of chondrocyte mitogen-activated protein kinases (MAPK) i...
The objective of this study was to evaluate the extent of stromal cell-derived factor-1's (SD... more The objective of this study was to evaluate the extent of stromal cell-derived factor-1's (SDF-1) involvement in the pathogenesis of idiopathic versus post-traumatic OA by comparing differences in synovial membrane morphology, SDF-1 synovial fluid (SF) concentrations, and matrix metalloproteinase-13 (MMP-13) SF concentrations. Thirty-six 3-month-old Hartley guinea pigs were obtained and divided into 6 groups. Upon sacrifice, India Ink staining was used to evaluate gross morphology, Safranin O/Fast green staining was used to assess cartilage damage, H/E staining was employed to visualize the synovium, and SF samples were obtained for biochemical analyses. Sandwich ELISA was used to quantify the SF concentrations of SDF-1 and MMP-13. 12 month-old, idiopathic OA guinea pigs and 5.5 month-old ACLT animals had comparable cartilage damage when evaluated by the Modified Mankin Score. SDF-1 and MMP-13 concentrations were not statistically different between the two groups. The synovial m...
The cytoskeleton network is believed to play an important role in the biomechanical properties of... more The cytoskeleton network is believed to play an important role in the biomechanical properties of the chondrocyte. Ours and other laboratories have demonstrated that chondrocytes exhibit a viscoelastic solid creep behavior in vitro and that viscoelastic properties decrease in osteoarthritic chondrocytes. In this study, we aimed to understand whether the alteration of viscoelastic properties is associated with changes in cytoskeleton components of ageing chondrocytes from rabbit knee articular cartilage. Three age groups were used for this study: young (2-months-old, N=23), adult (8-months-old, N=23), and old (31-months-old, N=23) rabbit groups. Cartilage structure and proteoglycan and type II collagen content were determined by H&E and Toluidine Blue staining, and type II collagen antibody. The detailed structure of the chondrocytes in all groups was visualized using transmission electron microscopy (TEM). Chondrocytes were isolated from full-thickness knee cartilage of rabbits from...
We have recently reported that ROCK1 deficiency in mouse embryonic fibroblasts (MEF) has superior... more We have recently reported that ROCK1 deficiency in mouse embryonic fibroblasts (MEF) has superior anti-apoptotic and pro-survival effects than antioxidants against doxorubicin, a chemotherapeutic drug. Although oxidative stress is the most widely accepted mechanism, our studies suggest that ROCK1-dependent actin cytoskeleton remodeling plays a more important role in mediating doxorubicin cytotoxicity on MEFs. To further explore the contributions of ROCK1-dependent actin cytoskeleton remodeling in response to stress, this study investigates the mechanistic differences between the cytotoxic effects of doxorubicin versus hydrogen peroxide (H2O2), with a focus on cytoskeleton alterations, apoptosis and necrosis induction. We found that both types of stress induce caspase activation but with different temporal patterns and magnitudes in MEFs: H2O2 induces the maximal levels (2 to 4-fold) of activation of caspases 3, 8, and 9 within 4 h, while doxorubicin induces much higher maximal levels (15 to 25-fold) of caspases activation at later time points (16-24 h). In addition, necrosis induced by H2O2 reaches maximal levels within 4 h while doxorubicin-induced necrosis largely occurs at 16-24 h secondary to apoptosis. Moreover, both types of stress induce actin cytoskeleton remodeling but with different characteristics: H2O2 induces disruption of stress fibers associated with cytosolic translocation of phosphorylated myosin light chain (p-MLC) from stress fibers, while doxorubicin induces cortical F-actin formation associated with cortical translocation of p-MLC from central stress fibers. Furthermore, N-acetylcysteine (an antioxidant) is a potent suppressor for H2O2-induced cytotoxic effects including caspase activation, necrosis, and cell detachment, but shows a much reduced inhibition on doxorubicin-induced changes. On the other hand, ROCK1 deficiency is a more potent suppressor for the cytotoxic effects induced by doxorubicin than by H2O2. These results support the notion that doxorubicin induces caspase activation, necrosis, and actin cytoskeleton alterations largely through ROCK1-dependent and oxidative stress-independent pathways.
Frontiers of Energy and Power Engineering in China, 2009
For grain in-store drying, a solar assisted drying process has been developed, which consists of ... more For grain in-store drying, a solar assisted drying process has been developed, which consists of a set including a solar-assisted heat pump, a ventilation system, a grain stirrer, etc. In this way, low power consumption, short cycle time and water content uniformity can be achieved in comparison with the conventional method. A solar-assisted heat pump drying system has been designed
Human urine-derived stem cells (hUSCs) are a newly found type of stem cell with a potential for t... more Human urine-derived stem cells (hUSCs) are a newly found type of stem cell with a potential for therapeutic application in urology. The aim of this study is to investigate whether hUSCs contribute to cartilage regeneration. Despite their characterization with multi-lineage differentiation capacities, in terms of osteogenesis, adipogenesis and myogenesis, hUSCs do not show the ability to differentiate into chondrocytes. Human bone marrow stromal cells (hBMSCs) are a tissue-specific stem cell for endochondral bone formation; however, repeated-passage hBMSCs have a lower capacity for chondrogenic differentiation. We found that the extracellular matrix (ECM) deposited by hUSCs (UECM) can greatly recharge repeated-passage hBMSCs toward chondrogenic differentiation, a result that might be explained by trophic factors released from hUSCs being immobilized in UECM. We also found that ECM from repeated-passage hBMSCs (BECM) have a limited rejuvenation effect. The Wnt11-mediated noncanonical ...
Chondrosarcoma is the most common primary malignant bone tumor in adults, has no effective system... more Chondrosarcoma is the most common primary malignant bone tumor in adults, has no effective systemic treatment, and patients with this disease have poor survival. Altered expression of microRNA (miR) is involved in tumorigenesis, however its role in chondrosarcoma is undetermined. MicroRNA-181a is overexpressed in high grade chondrosarcoma, is upregulated by hypoxia, and increases VEGF expression. Here, the purpose was to determine the mechanism of miR-181a regulation of VEGF, determine if miR-181a overexpression promotes tumor progression, and to evaluate an antagomir-based approach for chondrosarcoma treatment. Therapeutic inhibition of miR-181a decreased expression of VEGF and MMP1 in vitro, and angiogenesis, MMP1 activity, tumor growth, and lung metastasis, all by more than 50%, in a xenograft mouse model. A target of miR-181a is regulator of G-protein signaling 16 (RGS16), a negative regulator of CXC chemokine receptor 4 (CXCR4) signaling. CXCR4 signaling is increased in chondro...
Alterations of genes encoding transcriptional regulators of lymphoid development are a hallmark o... more Alterations of genes encoding transcriptional regulators of lymphoid development are a hallmark of B-progenitor acute lymphoblastic leukemia (B-ALL), and most commonly involve PAX5, encoding the DNA-binding transcription factor paired-box 5. The majority of PAX5 alterations in ALL are heterozygous, and key PAX5 target genes are expressed in leukemic cells, suggesting that PAX5 may be a haploinsufficient tumor suppressor. To examine the role of PAX5 alterations in leukemogenesis, we performed mutagenesis screens of mice heterozygous for a loss-of-function Pax5 allele. Both chemical and retroviral mutagenesis resulted in a significantly increased penetrance and reduced latency of leukemia, with a shift to B-lymphoid lineage. Genomic profiling identified a high frequency of secondary genomic mutations, deletions and retroviral insertions targeting B-lymphoid development, including Pax5, and additional genes and pathways mutated in ALL, including tumor suppressors, Ras and JAK-STAT sign...
The Hedgehog (Hh) family of proteins consists of Indian hedgehog (Ihh), sonic hedgehog (Shh), and... more The Hedgehog (Hh) family of proteins consists of Indian hedgehog (Ihh), sonic hedgehog (Shh), and desert hedgehog (Dhh). These proteins serve as essential regulators in a variety of developmental events. Ihh is mainly produced and secreted by prehypertrophic chondrocytes and regulates chondrocyte hypertrophy and endochondral bone formation during growth plate development. Tissue-specific deletion of the Ihh gene (targeted by Col2a1-Cre) causes early lethality in mice. Transgenic mice with induced Ihh expression exhibit increased chondrocyte hypertrophy and cartilage damage resembling human osteoarthritis (OA). During OA development, chondrocytes recapitulate the differentiation process that happens during the fetal status and which does not occur to an appreciable degree in adult articular cartilage. Ihh expression is up-regulated in human OA cartilage, and this upregulation correlates with OA progression and changes in chondrocyte morphology. A genetic study in mice further showed ...
Ouabain is a common tool to explore the pathophysiological changes in adult mammalian cochlea in ... more Ouabain is a common tool to explore the pathophysiological changes in adult mammalian cochlea in vivo. In prior studies, locally administering ouabain via round window membrane demonstrated that the ototoxic effects of ouabain in vivo varied among mammalian species. Little is known about the ototoxic effects in vitro. Thus, we prepared cochlear organotypic cultures from postnatal day-3 rats and treated these cultures with ouabain at 50, 500, and 1000 μM for different time to elucidate the ototoxic effects of ouabain in vitro and to provide insights that could explain the comparative ototoxic effects of ouabain in vivo. Degeneration of cochlear hair cells and spiral ganglion neurons was evaluated by hair-cell staining and neurofilament labeling, respectively. Annexin V staining was used to detect apoptotic cells. A quantitative RT-PCR apoptosis-focused gene array determined changes in apoptosis-related genes. The results showed that ouabain-induced damage in vitro was dose and time d...
Osteoarthritis (OA) is closely associated with aging, but its underlying mechanism is unclear. Re... more Osteoarthritis (OA) is closely associated with aging, but its underlying mechanism is unclear. Recent publications were reviewed to elucidate the connection between aging and OA. With increasing OA incidence, more senior people are facing heavy financial and social burdens. Age-related OA pathogenesis is not well understood. Recently, it has been realized that age-related changes in other tissues besides articular cartilage may also contribute to OA development. Many factors including senescence-related secretory phenotypes, chondrocytes' low reactivity to growth factors, mitochondrial dysfunction and oxidative stress, and abnormal accumulation of advanced glycation end products (AGEs) may all play key roles in the pathogenesis of age-related OA. Lately, epigenetic regulation of gene expression was recognized for its impact on age-related OA pathogenesis. Up to now, few studies have been reported about the role of miRNA and long-noncoding RNA (lncRNA) in age-related OA. Research...
Genetically engineered mouse models (GEMMs) of human cancer are important for advancing our under... more Genetically engineered mouse models (GEMMs) of human cancer are important for advancing our understanding of tumor initiation and progression as well as for testing novel therapeutics. Retinoblastoma is a childhood cancer of the developing retina that initiates with biallelic inactivation of the RB1 gene. GEMMs faithfully recapitulate the histopathology, molecular, cellular, morphometric, neuroanatomical and neurochemical features of human retinoblastoma. In this study, we analyzed the genomic and epigenomic landscape of murine retinoblastoma and compared them to human retinoblastomas to gain insight into shared mechanisms of tumor progression across species. Similar to human retinoblastoma, mouse tumors have low rates of single nucleotide variations. However, mouse retinoblastomas have higher rates of aneuploidy and regional and focal copy number changes that vary depending on the genetic lesions that initiate tumorigenesis in the developing murine retina. Furthermore, the epigenet...
Zhonghua wai ke za zhi [Chinese journal of surgery], Jan 15, 2007
To investigate the properties of screw-bone interface of expansive pedicle screw (EPS) in osteopo... more To investigate the properties of screw-bone interface of expansive pedicle screw (EPS) in osteoporotic sheep using micro-CT and histology. Six female sheep with bilateral ovariectomy-induced osteoporosis were employed in this experiment and were randomly assigned into 2 groups: A and B. After EPS insertion in each femoral condyles, sheep in group A were bred for 3 months, while those in group B 6 months. Femoral condyles with EPS were 3D-imaged and reconstructed by micro-CT. Histology was evaluated thereafter. The trabecular microstructure was denser at the screw-bone interface than in the distant parts in expansive section, especially within spiral marking. In the non-expansive section, however, there was no significant difference between the interface and the distant parts. The regions of interest (ROI) adjacent to EPS were reconstructed and analyzed by micro-CT using the same thresholds. The 3D-parameters generated, including tissue mineral density (TMD), bone volume fraction (BV...
One of the hallmarks of osteoarthritic cartilage is the loss of chondrocyte cellularity due to ce... more One of the hallmarks of osteoarthritic cartilage is the loss of chondrocyte cellularity due to cell death. However, considerable controversy has recently arisen surrounding the extent of apoptotic cell death involved in development of osteoarthritis (OA). To shed light on this issue, we characterized cell death in primary OA chondrocytes mediated by the CD95 (Fas) pathway. Treatment of chondrocytes with anti-CD95 not only increased the rate of cell death but also increased the production of CD95 ligand by chondrocytes. This reveals a novel autocrine regulatory loop whereby activated chondrocytes may amplify CD95 signals by inducing synthesis of CD95 ligand. Multiple morphologic detection analyses indicated that apoptosis accounted for only a portion of chondrocyte death, whereas the other chondrocytes died by necrosis. Both chondrocyte apoptosis and necrosis depended on the activity of p38 mitogen-activated protein kinase (MAPK) within chondrocytes. Treatment of chondrocytes with th...
Histone deacetylase 4 (HDAC4) is a critical negative regulator for chondrocyte hypertrophy by bin... more Histone deacetylase 4 (HDAC4) is a critical negative regulator for chondrocyte hypertrophy by binding to and inhibiting Runx2, a critical transcription factor for chondrocyte hypertrophy. It is unclear how HDAC4 expression and stability are regulated during growth plate development. We report here that inhibition of mitogen-activated protein kinase (MAPK) p38 by dominant negative p38 or p38 inhibitor prevents HDAC4 degradation. Mutation of a potential caspase-2 and 3 cleavage site Asp289 stabilizes HDAC4 in chondrocytes. In contrast, constitutively active MAPK kinase 6 (constitutive activator of p38) transgenic mice exhibit decreased HDAC4 content in vivo. We also observed that p38 stimulates caspase-3 activity in chondrocytes. Inhibition of p38 or caspases reduced HDAC4 degradation. HDAC4 inhibited Runx2 promoter activity in a dose-dependent manner and caspase inhibitors further enhanced this inhibition by preventing HDAC4 degradation. Overall, these results demonstrate that p38 pr...
It had been found that the concentration of chemokine stromal cell-derived factor-1 (SDF-1) was s... more It had been found that the concentration of chemokine stromal cell-derived factor-1 (SDF-1) was significantly higher in synovial fluid (SF) of patients with osteoarthritis (OA; > or = 200 ng/ml) and rheumatoid arthritis (RA; > or = 700 ng/ml) compared to controls (< or = 100 ng/ml). Our aim was to determine whether the pathological concentration of SDF-1 induces chondrocyte death and to investigate mechanisms underlying such death. Human OA chondrocytes were treated with different doses of SDF-1, or in combination with SF from patients with arthritis. Apoptotic and necrotic cells were labeled by annexin V and propidium iodide, respectively, and quantified by FACS analysis. Caspase-3 activity was quantified by a plate absorbance assay, and matrix metalloproteinase 13 mRNA levels were determined by RT-PCR. The release of high mobility group box chromatin protein 1, a specific marker of cell necrosis, and the activities of chondrocyte mitogen-activated protein kinases (MAPK) i...
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