- 4635 Second Avenue Suite 2000
Sacramento CA 95817 - 916-734-5015
Dominik Haudenschild
University of California, Davis, Orthopaedic Surgery, Faculty Member
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Research Interests: Engineering, Chemistry, Cell Biology, Medicine, Manganese, and 15 moreExtracellular Matrix, Biological Sciences, Cell line, Humans, Mice, Bone, Animals, Alkaline phosphatase, Osteogenesis, Protein Binding, Cations, Mesenchymal Stromal Cells, Biochemistry and cell biology, choristoma, and Medical and Health Sciences
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Knee injuries cause structural damage and acute inflammation that initiates the development of post-traumatic osteoarthritis (PTOA). NADPH oxidase 4 (Nox4), a member of a family of enzymes that generates reactive oxygen species (ROS),... more
Knee injuries cause structural damage and acute inflammation that initiates the development of post-traumatic osteoarthritis (PTOA). NADPH oxidase 4 (Nox4), a member of a family of enzymes that generates reactive oxygen species (ROS), plays a pivotal role in normal development of the musculoskeletal system, but may increase ROS production to harmful levels after joint injury. The role of ROS in both normal joint homeostasis and injury is poorly understood, but inhibition of excessive ROS production by Nox4 after joint injury could be protective to the joint, decreasing oxidative stress and the initiation of PTOA. Knee injuries were simulated using inflammatory cytokines in cultured primary human chondrocytes and a non-invasive mouse model of PTOA in C57BL/6N and Nox4 knockout mice. There is an acute decrease in Nox4 activity within 24 hours after injury in both systems, followed by a subsequent sustained low-level increase, a novel finding not seen in any other system. Inhibition of Nox4 activity by GKT137831 was protective against early structural changes after non-invasive knee injury in a mouse model. Nox4 knockout mice had significant differences in structural and mechanical properties of bone, providing further evidence for the role of Nox4 in the development of joint tissues and biochemical response after joint injury. Nox4 plays a significant role in the acute phase after joint injury, and targeted inhibition of inflammation caused by Nox4 may be protective against early joint changes in the pathogenesis of PTOA.
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Chondrocytes that were isolated from adult human articular cartilage changed phenotype during monolayer tissue culture, as characterized by a fibroblastic morphology and cellular proliferation. Increased proliferation was accompanied by... more
Chondrocytes that were isolated from adult human articular cartilage changed phenotype during monolayer tissue culture, as characterized by a fibroblastic morphology and cellular proliferation. Increased proliferation was accompanied by downregulation of the cartilage‐specific extracellular matrix proteoglycan, aggrecan, by cessation of type‐II collagen expression, and by upregulation of type‐I collagen and versican. This phenomenon observed in monolayer was reversible after the transfer of cells to a suspension culture system. The transfer of chondrocytes to suspension culture in alginate beads resulted in the rapid upregulation of aggrecan and type‐II collagen and the downregulation of expression of versican and type‐I collagen. Type‐X collagen and osteopontin, markers of chondrocyte hypertrophy and commitment to endochondral ossification, were not expressed by adult articular chondrocytes cultured in alginate, even after 5 months. In contrast, type‐X collagen was expressed within 2 weeks in a population of cells derived from a fetal growth plate. The inability of adult articular chondrocytes to express markers of chondrocyte hypertrophy has underscored the fundamental distinction between the differentiation pathways that lead to articular cartilage or to bone. Adult articular chondrocytes expressed only hyaline articular cartilage markers without evidence of hypertrophy.
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Supplementary Figure 1 from Interleukin-17 Receptor-Like Gene Is a Novel Antiapoptotic Gene Highly Expressed in Androgen-Independent Prostate Cancer
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Research Interests: Biomedical Engineering, Biology, Biorheology, Cell Biology, Medicine, and 14 moreGene expression, Cytoskeleton, Signal Transduction, Humans, Compressive Strength, Phosphorylation, Actin Cytoskeleton, Clinical Sciences, Nitric Oxide Synthase, Chondrocytes, Focal Adhesions, cofilin, Cell culture techniques, and Nitric oxide synthase type II
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The actin cytoskeleton is a dynamic network required for intracellular transport, signal transduction, movement, attachment to the extracellular matrix, cellular stiffness and cell shape. Cell shape and the actin cytoskeletal... more
The actin cytoskeleton is a dynamic network required for intracellular transport, signal transduction, movement, attachment to the extracellular matrix, cellular stiffness and cell shape. Cell shape and the actin cytoskeletal configuration are linked to chondrocyte phenotype with regard to gene expression and matrix synthesis. Historically, the chondrocyte actin cytoskeleton has been studied after formaldehyde fixation--precluding real-time measurements of actin dynamics, or in monolayer cultured cells. Here we characterize the actin cytoskeleton of living low-passage human chondrocytes grown in three-dimensional culture using a stably expressed actin-GFP construct. GFP-actin expression does not substantially alter the production of endogenous actin at the protein level. GFP-actin incorporates into all actin structures stained by fluorescent phalloidin, and does not affect the actin cytoskeleton as seen by fluorescence microscopy. GFP-actin expression does not significantly change the chondrocyte cytosolic stiffness. GFP-actin does not alter the gene expression response to cytokines and growth factors such as IL-1beta and TGF-beta. Finally, GFP-actin does not alter production of extracellular matrix as measured by radiosulfate incorporation. Having established that GFP-actin does not measurably affect the chondrocyte phenotype, we tested the hypothesis that IL-1beta and TGF-beta differentially alter the actin cytoskeleton using time-lapse microscopy. TGF-beta increases actin extensions, and lamellar ruffling indicative of Rac/CDC42 activation, while IL-1beta causes cellular contraction indicative of RhoA activation. The ability to visualize GFP-actin in living chondrocytes in 3D culture without disrupting the organization or function of the cytoskeleton is an advance in chondrocyte cell biology and provides a powerful tool for future studies in actin-dependent chondrocyte differentiation and mechanotransduction pathways.
Research Interests: Biology, Cell Biology, Mechanobiology, Confocal Microscopy, Medicine, and 15 moreGene expression, Extracellular Matrix, Cytoskeleton, Humans, Pubmed, Profilin, Actin Cytoskeleton, Cell Shape, Chondrocytes, Cellular and Molecular Neuroscience, Sulfates, Interleukin, reverse transcriptase polymerase chain reaction, Cell culture techniques, and Nitric oxide synthase type II
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The novel coronavirus disease 2019 (COVID‐19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and has infected more than 650 million people worldwide. Approximately 23% of these patients developed lasting... more
The novel coronavirus disease 2019 (COVID‐19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and has infected more than 650 million people worldwide. Approximately 23% of these patients developed lasting “long‐haul” COVID symptoms, including fatigue, joint pain, and systemic hyperinflammation. However, the direct clinical impact of SARS‐CoV‐2 infection on the skeletal system including bone and joint health has not been determined. Utilizing a humanized mouse model of COVID‐19, this study provides the first direct evidence that SARS‐CoV‐2 infection leads to acute bone loss, increased osteoclast number, and thinner growth plates. This bone loss could decrease whole‐bone mechanical strength and increase the risk of fragility fractures, particularly in older patients, while thinner growth plates may create growth disturbances in younger patients. Evaluating skeletal health in patients that have recovered from COVID‐19 will be crucial to identify at‐risk popula...
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Effect of alendronate on post-traumatic osteoarthritis induced by anterior cruciate following non-invasive knee injury, but was not able to mitigate long-term joint degeneration. These data contribute
oncogene LRF is a survival factor in chondrosarcoma and contributes to tumor
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OBJECTIVE Joint injury rapidly induces expression of primary response genes (PRGs), which activate a cascade of secondary genes that destroy joint tissues and initiate post-traumatic osteoarthritis (PTOA). Bromodomain-containing-protein-4... more
OBJECTIVE Joint injury rapidly induces expression of primary response genes (PRGs), which activate a cascade of secondary genes that destroy joint tissues and initiate post-traumatic osteoarthritis (PTOA). Bromodomain-containing-protein-4 (Brd4) and cyclin-dependent-kinase-9 (CDK9) cooperatively control the rate-limiting step of PRG transactivation, including pro-inflammatory genes. This study investigated whether Brd4 and CDK9 inhibitors suppress inflammation and prevent PTOA development in vitro and in a mouse PTOA model. METHODS The effects of Brd4 and CDK9 inhibitors (JQ1 and Flavopiridol) on PRG and associated secondary damage were rigorously tested in different settings. Short-term effects of inflammatory stimuli (IL-1β, IL-6, TNF) on human chondrocyte PRG expression were assessed by RT-PCR and microarray after 5-h. We quantified glycosaminoglycan release from IL-1β-treated bovine cartilage explants after 3-6 days, and osteoarthritic changes in mice after ACL-rupture using RT-PCR (2-24hrs), in vivo imaging of MMP activity (24hrs), AFM-nanoindentation (3-7days), and histology (3days-4wks). RESULTS Flavopiridol and JQ1 inhibitors act synergistically, and a combination of both almost completely prevented the activation of most IL-1β-induced PRGs in vitro by microarray analysis, and prevented IL-1β-induced glycosaminoglycan release from cartilage explants. . Mice given the drug combination showed reduced IL-1β and IL-6 expression, less in vivo MMP activity, and lower synovitis (1.5 vs 4.9) and OARSI scores (2.8 vs 6.0) than untreated mice with ACL-rupture. CONCLUSIONS JQ1 and Flavopiridol work synergistically to reduce injury response after joint trauma, suggesting that targeting Brd4 and/or CDK9 could be a viable strategy for PTOA prevention and treatment of early OA.
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OBJECTIVE Joint injury rapidly induces expression of primary response genes (PRGs), which activate a cascade of secondary genes that destroy joint tissues and initiate post-traumatic osteoarthritis (PTOA). Bromodomain-containing-protein-4... more
OBJECTIVE Joint injury rapidly induces expression of primary response genes (PRGs), which activate a cascade of secondary genes that destroy joint tissues and initiate post-traumatic osteoarthritis (PTOA). Bromodomain-containing-protein-4 (Brd4) and cyclin-dependent-kinase-9 (CDK9) cooperatively control the rate-limiting step of PRG transactivation, including pro-inflammatory genes. This study investigated whether Brd4 and CDK9 inhibitors suppress inflammation and prevent PTOA development in vitro and in a mouse PTOA model. METHODS The effects of Brd4 and CDK9 inhibitors (JQ1 and Flavopiridol) on PRG and associated secondary damage were rigorously tested in different settings. Short-term effects of inflammatory stimuli (IL-1β, IL-6, TNF) on human chondrocyte PRG expression were assessed by RT-PCR and microarray after 5-h. We quantified glycosaminoglycan release from IL-1β-treated bovine cartilage explants after 3-6 days, and osteoarthritic changes in mice after ACL-rupture using RT-PCR (2-24hrs), in vivo imaging of MMP activity (24hrs), AFM-nanoindentation (3-7days), and histology (3days-4wks). RESULTS Flavopiridol and JQ1 inhibitors act synergistically, and a combination of both almost completely prevented the activation of most IL-1β-induced PRGs in vitro by microarray analysis, and prevented IL-1β-induced glycosaminoglycan release from cartilage explants. . Mice given the drug combination showed reduced IL-1β and IL-6 expression, less in vivo MMP activity, and lower synovitis (1.5 vs 4.9) and OARSI scores (2.8 vs 6.0) than untreated mice with ACL-rupture. CONCLUSIONS JQ1 and Flavopiridol work synergistically to reduce injury response after joint trauma, suggesting that targeting Brd4 and/or CDK9 could be a viable strategy for PTOA prevention and treatment of early OA.
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A table-top microdevice was introduced in this work to produce ultrasmall particles for drug delivery via inhalation. The design and operation are similar to that of spray-drying equipment used in industry, but the device itself is much... more
A table-top microdevice was introduced in this work to produce ultrasmall particles for drug delivery via inhalation. The design and operation are similar to that of spray-drying equipment used in industry, but the device itself is much smaller and more portable in size, simpler to operate and more economical. More importantly, the device enables more accurate control over particle size. Using Flavopiridol, an anti-inflammation medication, formulations have been developed to produce inhalable particles for pulmonary delivery. A solution containing the desired components forms droplets by passing through an array of micro-apertures that vibrate via a piezo-electrical driver. High-purity nitrogen gas was introduced and flew through the designed path, which included the funnel collection and cyclone chamber, and finally was pumped away. The gas carried and dried the micronized liquid droplets along the pathway, leading to the precipitation of dry solid microparticles. The formation of ...
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A table-top microdevice was introduced in this work to produce ultrasmall particles for drug delivery via inhalation. The design and operation are similar to that of spray-drying equipment used in industry, but the device itself is much... more
A table-top microdevice was introduced in this work to produce ultrasmall particles for drug delivery via inhalation. The design and operation are similar to that of spray-drying equipment used in industry, but the device itself is much smaller and more portable in size, simpler to operate and more economical. More importantly, the device enables more accurate control over particle size. Using Flavopiridol, an anti-inflammation medication, formulations have been developed to produce inhalable particles for pulmonary delivery. A solution containing the desired components forms droplets by passing through an array of micro-apertures that vibrate via a piezo-electrical driver. High-purity nitrogen gas was introduced and flew through the designed path, which included the funnel collection and cyclone chamber, and finally was pumped away. The gas carried and dried the micronized liquid droplets along the pathway, leading to the precipitation of dry solid microparticles. The formation of ...
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Procede de determination de la presence de types cellulaires specifiques dans une population cellulaire mixte. Ce procede consiste a identifier et a detecter des marqueurs pour les types cellulaires cibles, a preparer des amorces... more
Procede de determination de la presence de types cellulaires specifiques dans une population cellulaire mixte. Ce procede consiste a identifier et a detecter des marqueurs pour les types cellulaires cibles, a preparer des amorces specifiques des marqueurs, et a utiliser la technologie de la reaction a transcriptase inverse dans le but d'amplifier et de detecter ces marqueurs. Ledit procede est suffisamment sensible pour detecter la presence d'a peine 100 cellules cibles dans une population cellulaire. Les cellules cibles peuvent etre des chondrocytes humains et des keratinocytes humains.
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Bone morphogenetic protein-2 (BMP2), a member of the transforming growth factor-β family, is known to induce osteogenic differentiation among chondrocytes, osteoprogenitor cells, and human mesenchymal stem cells. Pentameric cartilage... more
Bone morphogenetic protein-2 (BMP2), a member of the transforming growth factor-β family, is known to induce osteogenic differentiation among chondrocytes, osteoprogenitor cells, and human mesenchymal stem cells. Pentameric cartilage oligomerization matrix protein (COMP) binds BMP2 and presents it to the receptors of C2C12 cells. Our prior investigation indicates that the COMP+BMP2 complex enhances the activity of BMP2 in the context of osteogenic differentiation via the Smad pathway. This presentation provides a more molecular level and single cell level look into the mechanism of this enhancement. Using multimodal and multifunctional approach of atomic force microscopy image, single cell mechanics, and confocal imaging, our investigation reveals that treatment of COMP+BMP2 to C2C12 increases the stiffness of the cell membrane and appearance of fiber-like features on the cells. Strong presence of actin stress fibers at the basal interface of the cells and the rearrangement and form...
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In inflammatory arthritis, the dysregulation of osteoclast activity by proinflammatory cytokines, including TNF, interferes with bone remodeling during inflammation through Ca2+-dependent mechanisms causing pathological bone loss.... more
In inflammatory arthritis, the dysregulation of osteoclast activity by proinflammatory cytokines, including TNF, interferes with bone remodeling during inflammation through Ca2+-dependent mechanisms causing pathological bone loss. Ca2+-dependent CREB/c-fos activation via Ca2+-calmodulin kinase IV (CaMKIV) induces transcriptional regulation of osteoclast-specific genes via NFATc1, which facilitate bone resorption. In leukocytes, Ca2+ regulation of NFAT-dependent gene expression oftentimes involves the activity of the Ca2+-activated K+ channel KCa3.1. In this study, we evaluate KCa3.1 as a modulator of Ca2+-induced NFAT-dependent osteoclast differentiation in inflammatory bone loss. Microarray analysis of receptor activator of NF-κB ligand (RANKL)-activated murine bone marrow macrophage (BMM) cultures revealed unique upregulation of KCa3.1 during osteoclastogenesis. The expression of KCa3.1 in vivo was confirmed by immunofluorescence staining on multinucleated cells at the bone surfac...
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The oncogene leukemia/lymphoma-related factor (LRF) enhances chondrosarcoma proliferation and malignancy. This study aimed to investigate the roles of LRF in chondrogenic differentiation of primary human bone marrow-derived mesenchymal... more
The oncogene leukemia/lymphoma-related factor (LRF) enhances chondrosarcoma proliferation and malignancy. This study aimed to investigate the roles of LRF in chondrogenic differentiation of primary human bone marrow-derived mesenchymal stem cells (BMSCs). LRF was overexpressed in BMSC by lentiviral transduction. Chondrogenic differentiation of BMSC was induced by high-density pellet culture. Western blotting and real-time polymerase chain reaction were used to investigate changes in protein and mRNA levels, respectively, during chondrogenesis. Safranin-O staining, immunohistochemistry, and glycoaminoglycan contents were used to assess cartilage matrix deposition. BMSC proliferation was determined by mitochondrial dehydrogenase activity and cell counting. Cell cycle profiling was performed by flow cytometry. LRF overexpression effectively inhibited protein and mRNA expression of chondrocyte markers and cartilage matrix deposition during chondrogenesis of BMSC. Endogenous LRF expressi...