Department of Orthopaedic Surgery, School of Medicine
Department of Orthopaedic Surgery, School of Medicine
Mechanotransduction and Osteoarthritis Research Laboratory, combining basic science with clinical and translational impact.
Primary Response to Joint Injury in Osteoarthritis: Animal Models and Biomarkers
Osteoarthritis is a painful and debilitating disease that results in loss of joint function. Because cartilage is an aneural and avascular tissue, patients often do not seek medical advice until there is irreversible loss of cartilage. At that stage, painful bone-bone contact occurs in the joints. Knee and hip osteoarthritis is often the end-stage result of silent pain-free chronic cartilage degradation that occurs over years or even decades. A portion of my lab is dedicated to identifying serum biomarkers of this pre-arthritic cartilage degradation. The goal is to create a screen which can be routinely used by physicians to identify patients at risk for joint failure due to osteoarthritis, in a similar fashion as serum cholesterol levels are currently used to identify patients with silent cardiovascular disease that are at risk for heart failure or stroke. Minor joint injuries, such as an ACL or meniscus tear, ultimately lead to arthritis in most cases. The damage that initiates arthritis begins almost immediately at the cellular level. Despite this, current clinical care of ACL tears does not address the initial damage that leads to future arthritis. We have developed a non-surgical mouse model of ACL tears, in which we study the cellular responses to this type of injury, with the goal of developing intervention strategy at the time of injury to prevent future arthritis.
Most people understand that lifting weights will increase muscle mass, loss of activity causes unused muscles to shrink, and too much activity can lead to injury. It turns out that the same is true for cartilage: moderate mechanical loads are required for cartilage homeostasis. Too little, or excessive loading causes cartilage matrix to be lost or damaged. Mechanotransduction is the process through which cells within cartilage sense the mechanical forces and convert them to biochemical signals. A portion of my lab studies mechanotransduction, the interactions between the chondrocyte cytoskeleton and signal transduction events which lead to the regulation of gene expression and extracellular matrix synthesis that is required for the maintenance of health cartilage.
Growth Factor-Matrix Interactions
The extracellular matrix can provide a molecular "context" to growth factors that affects the cellular responses. Our recent discovery is that Cartilage Oligomeric Matrix Protein (COMP) is a multivalent TGF-beta binding protein, and that COMP-bound TGF-beta has more activity than free unbound TGF-beta. The same is true for Bone Morphogenetic Proteins (BMPs). We are exploring the ability of COMP to augment BMP and TGF-beta activity in cartilage and bone tissue engineering applications, and mapping the binding exact binding site to get a better understanding of the mechanisms involved.
Grad Group Affiliations
- Biochemistry, Molecular, Cellular and Developmental Biology
- Biomedical Engineering Graduate Group
Specialties / Focus
- Cell Biology
- Differentiation, Morphogenesis and Wound Healing
- Gene Regulation
- Molecular Medicine
- Signal Transduction
- Stem Cell Biology
- Structural Biology
- Rotations MCB 220L MCB Rotation Course, 2017 Fall, 2018 Winter
- Seminar BIM298D Seminar Based Discussion of Current Topics in Orthopaedic Research, Spring 2018
- Haudenschild http://lab.haudenschild.org
- Dominik Haudenschild PI; Jasper Yik, Ph.D. - Project Scientist;Tomoaki Fukui, MD, Ph.D., - Post-doctoral Fellow;Adam Wegner - MD, Ph.D., - Research Resident;Jeffrey Lu - Ph.D. Candidate BMEGG; Michael Fong - Ph.D. Student BMEGG;Michael Robbins - Medical StudentYasaman (Jasmin) Arabi - UC Davis Undergraduate volunteer;Maneesh Vij, Yale Undergraduate InternPrevious Lab Members2014 Elizabeth Tenborg - Research Specialist, Attending Veterinary School;2014 Nina Liu - Undergraduate volunteer;2014 Kie Shidara - Undergraduate volunteer;2013 Kazunari Ishida, M.D., Ph.D. - Post-doctoral Fellow, took position as practicing clinician at Kobe University in Japan;2013 Ethan Hu, M.D., Ph.D., - Post-doctoral Fellow;2012 Chitrangada Acharya Post-doctoral fellow, now at Allied Innovative Systems; 2011 Eunmee Hong, Post-doctoral fellow, Joined Orthopaedic Research Lab as post-doctoral fellow for Dr. Hari Reddi;2010 Kaylene Snow Junior Specialist; 2009 Derek Amanatullah Orthopaedic Surgery Fellow, Finishing Residency Training, Accepted Fellowship at Mayo Clinic;2013 Ashlene Kishore - Undergraduate Volunteer - applying to medical school;2012 Victoria Van Dinh Undergraduate Volunteer, applying to medical school;2012 Edward Yeh - UCD Undergraduate Volunteer - finishing degree;2012 Lawrence Lin UCD Undergraduate Volunteer - finishing degree;2012 Joanna Turkiewicz - UCD Undergraduate Volunteer - finishing degree;
- UC Davis Medical Center
Honors and Awards
- Arthritis Foundation
- Department of Defense
- NIH NIAMS R03
- NIH NIAMS R21
- Orthopaedic Trauma Association
- Orthopaedic Research and Education Foundation
- NIH NIAMS R01 through 2022
- Orthopaedic Research Society
- International Cartilage Repair Society
- OsteoArthritis Research Society International
- American Society for Bone and Mineral Research
- 2003 Ph.D. Biochemistry Molecular Biology UC Davis
- 1989 BA Biology Boston University
- Flavopiridol protects bone tissue by attenuating RANKL-induced osteoclast formation. Hu Z, Chen Y, Song L, Yik JHN, Haudenschild DR, and Shunwu Fan. Front. Pharmacol. 15 Feb 2018;
- Ca2+-Dependent Regulation of NFATc1 via KCa3.1 in Inflammatory Osteoclastogenesis. Grössinger EM, Kang M, Bouchareychas L, Sarin R, Haudenschild DR, Borodinsky LN, and Adamopoulos IE. The Journal of Immunology Dec 15, 2017;
- Stem Cells in Spinal Fusion. Robbins MA, Haudenschild DR, Wegner AM, and Klineberg EO. Global Spine J. 2017; Vol 8: pg 801-810.
- Inhibition of CDK9 prevents mechanical injury-induced inflammation, apoptosis and matrix degradation in cartilage explants. Hu Z, Yik JHN, Cissell DD, Michelier PV, Athanasiou KA, and Haudenschild DR. European Cells & Materials. 2016; Vol 30: pg 200-209.
- Binding to COMP Reduces the BMP2 Dose for Spinal Fusion in a Rat Model. Refaat M, Klineberg EO, Fong MC, Garcia TC, Leach JK, Haudenschild DR. Spine. Spine (Phila Pa 1976). 2016 Jul 15;41(14):E829-36
- Articular Cartilage Injury and Potential Remedies. Chubinskaya S, Haudenschild DR, Gasser S, Stannard J, Krettek C, Borrelli J Jr. J Orthop Trauma 2015 Dec;29 Suppl 12:S47-52.
- Binding to COMP Reduces the BMP2 Dose for Spinal Fusion in a Rat Model. Refaat M, Klineberg EO, Fong MC, Garcia TC, Leach JK, Haudenschild DR. Spine. ePublished 14 December.
- Inhibition of CDK9 prevents mechanical injury-induced inflammation, apoptosis and matrix degradation in cartilage explants. Hu Z, Yik JHN, Cissell DD, Michelier PV, Athanasiou KA, and Haudenschild DR. European Cells & Materials. 12 October 2015, Vol 30, pg 200-209.
- Closed Joint ACL Disruption in Murine Model of PTA, Christiansen BA, Yik JHN, and Haudenschild DR. Chapter 7 in book “Post-Traumatic Arthritis: Pathogenesis, Diagnosis and Management”, edited by Steve Olson and Farshid Guilak. Published July.
- Non-Invasive Mouse Models of Post-Traumatic Osteoarthritis. Christiansen BA, Guilak F, Lockwood KA, Olson SA, Pitsillides AA, Sandell LJ, Silva MJ, van der Meulen MC, and Haudenschild DR. Osteoarthritis & Cartilage. 2015 Oct;23(10):1627-38.
- In-vitro and in-vivo imaging of MMP activity in cartilage and joint injury. Fukui T, Tenborg E, Yik JHN, and Haudenschild DR. Biochem Biophys Res Commun, 2015 May 8;460(3):741-6.
- Effect of Alendronate on Post-Traumatic Osteoarthritis Induced by Anterior Cruciate Ligament Rupture in Mice. Khorasani MS, Diko S, Hsia AW, Anderson MJ, Genetos DC, Haudenschild DR, and Christiansen BA. Arthritis Research & Therapy 2015, 17:30, Published 16 February.
2014 "High abundant protein removal from rodent blood for biomarker discovery", BBRC
2014 "In Vivo Fluorescence Reflectance Imaging of Protease Activity in a Mouse Model of Post-Traumatic Osteoarthritis." Osteoarthritis & Cartilage
2014 "Cartilage Oligomeric Matrix Protein and its Binding Partners in the Cartilage Extracellular Matrix: Interaction, Regulation and Role in Chondrogenesis." Matrix Biol.
2014 "Cyclin-Dependent Kinase 9 inhibition protects cartilage from the catabolic effects of pro-inflammatory cytokines." Arthritis Rheumatol.
2014 "Comparison of loading rate-dependent injury modes in a murine model of post-traumatic osteoarthritis." Journal of Orthopaedic Research
2014 "The Effect of Noggin Interference in a Rabbit Posterolateral Spinal Fusion Model." European Spine Journal
2013 "The oncogene leukemia/lymphoma-related factor (LRF) stimulates proliferation of mesenchymal stem cells and inhibits their chondrogenic differentiation." Cartilage, 4(4): 329-338.
2013 "Effect of age and cytoskeletal elements on the indentation-dependent mechanical stiffness of chondrocytes." PLoS ONE
2013 "Cartilage Oligomeric Matrix Protein Enhances Osteogenesis by Directly Binding and Activating Bone Morphogenetic Protein-2." Bone
2013 "Interactions Between FGF21 and BMP-2 in Osteogenesis." Biochemical and Biophysical Research Communications
2013 "c-Maf Transcription Factor Regulates ADAMTS-12 Expression in Human Chondrocytes." Cartilage
2012 Musculoskeletal changes following non-invasive knee injury using a novel mouse model of post-traumatic osteoarthritis." Osteoarthritis & Cartilage, PMID: 22531459.
2012 "Identification of a 3Kbp Mechanoresponsive Promoter Region in the Human Cartilage Oligomeric Matrix Protein Gene." Tissue Engineering Part A, PMID:22764748.
2012 "The Oncogene LRF is a Survival Factor in Chondrosarcoma and Contributes to Tumor Malignancy and Drug Resistance." Carcinogenesis. PMID:22847180
2012 "Chondrogenic Potential and Homogeneity of Cell Populations of Donor and Recipient Cells in a Fresh Osteochondral Allograft: A Case Report." Haudenschild DR, Hong E, Hatcher SL, and A.A. Jamali. Journal of Bone and Joint Surgery
2011 "Enhanced Activity of TGF-ß1 Bound to Cartilage Oligomeric Matrix Protein." Li H, Haudenschild DR, Di Cesare PE, Posey K, Hecht J, and Yik JHN. Journal of Biological Chemistry
2011 "Comparative Analysis with Collagen Type II Distinguioshes Cartilage Oligomeric Matrix Protein as a Primary TGF-ß-Responsive Gene." Osteoarthritis Cartilage.
2011 "Vimentin contributes to changes in chondrocyte stiffness in osteoarthritis." Haudenschild DR, Chen J, Pang N, Steklov N, Grogan SP, Lotz MK, D'Lima DD. Journal of Orthopaedic Research
2011 "Role of c-Maf in Chondrocyte Differentiation: A Review." Eunmee Hong, Paul E. Di Cesare, and Dominik R. Haudenschild. Cartilage
2010 "Rho Kinase-Dependent Activation of SOX9 in Chondrocytes", Arthritis & Rheumatism
2009 "Characterization of the Chondrocyte Actin Cytoskeleton in Living Three-Dimensional Culture: Response to Anabolic and Catabolic Stimuli" Molecular Cellular Biomechanics
2008 Rho Kinase-Dependent CCL20 Induced by Dynamic Compression of Human Chondrocytes." Arthritis & Rheumatism
2008 "Dynamic Compression of Chondrocytes Induces a Rho Kinase-Dependent Reorganization of the Actin Cytoskeleton." Biorheology.
2008 "Immunolocalization of IL-17A, IL-17B, and Their Receptors in Chondrocytes During Fracture Healing" Journal of Histochemistry & Cytochemistry
2006 "Interleukin-17 Receptor-Like Gene is a Novel Anti-apoptotic Gene Highly Expressed in Androgen-Independent Prostate Cancer" Cancer Research
2006 "Generation of Interleukin-17 Receptor-Like Protein (IL-17RL) in Prostate by Alternative Splicing of RNA" The Prostate
2006 "Bone Morphogenetic PRotein (BMP)-6 Signaling and BMP Antagonist Noggin in Prostate Cancer". Cancer Research
2003 "Interleukin-17 Family and IL-17 Receptors." Cytokine & Growth Factor Reviews
2002 "Soluble and Transmembrane Isoforms of Novel Interleukin-17 Receptor-like Protein by RNA splicing and Expression in Prostate Cancer". Journal of Biological Chemistry
2001 "Differential Expression of Multiple Genes During Articular Chondrocyte Redifferentiation". Anatomical Record
2000 "BMP Family" Review
1998 "Expression of a Stable Articular Cartilage Phenotype without Evidence of Hypertrophy by Adult Human Articular Chondrocytes in Vitro." Journal of Orthopaedic Research
1996 Cartilage Matrix Protein: Expression Patterns in Chicken, Mouse, and Human." Annals New York Academy of Sciences
1995 The Role of Coiled-Coil alpha-Helices and Disulfide Bonds in the Assembly and Stabilization of Cartilage Matrix Protein Subunits: A mutational Analysis." Journal of Biological Chemistry
1995 "Progression and Recapitulation of the Chondrocyte Differentiation Program: Cartilage Matrix Protein is a Marker for Cartilage Maturation." Developmental Biology
1995 "Cartilage Matrix Protein Forms a Type II Collagen-independent Filamentous Network: Analysis in Primary Cell Cultures with a Retrovirus Expression System." Molecular Biology of the Cell
1994 "Link Protein is Ubiquitously Expressed in Non-cartilagenous Tissues Where it Enhances and Stabilizes the Interaction of Proteoglycans with Hyaluronic Acid." Journal of Biological Chemistry