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Department of Orthopedics

Department of Orthopedics
 

Molecular Biology Lab

Researching Degenerative Joint Diseases


King
Karen B. King, PhD

Lab Director - Karen B. King, PhD

 

The long-term goals of the research in this laboratory are to elucidate the causes of the initiation and progression of osteoarthritis and other degenerative joint diseases and to create and improve treatment and prevention strategies. The approach is multi-disciplinary using techniques from molecular biology, biochemistry, mechanobiology, cell biology, biomarker analysis, imaging, biomechanics, and tissue engineering.

We study in vivo cyclical joint loading using a novel animal model of repetitive finger joint flexion. Force and frequency are precisely controlled, and outcome measures include histological analysis of cartilage and bone morphology, biochemical and spectral characterization of extracellular matrix components, and analysis of mechanical properties. Using this model, we identified a significant increase in proteoglycan in the cartilage deep zone (measured using Fourier-transform infrared microspectroscopy). We also mesasured an increase in the number of chondrocytes producing osteopontin, a protein involved in mineralization.

 

The laboratory collaborates with the Musculoskeletal Disorders Lab in identifying inflammatory agents in soft tissue exposed to cyclic and static loading.

Facilities

1,600 square feet of laboratory space
300 square foot cold room
Access to electronic and mechanical shops

Equipment

Animal anesthesia equipment
Electrical muscle stimulator, A/D board, amplifier, data acquisition workstation, load cells
HPLC workstation, software, auto-sampler, dual pumps, UV detector, fluorescence detector
Vacuum centrifuge concentrator
Multi-well plate reader with workstation and data analysis software, multi-well plate washer, multi-well plate shaker
Histology tissue processor, paraffin embedder, rotary microtome, slide dryer
Light and fluorescence microscope, digital camera, digital imaging and image analysis software
Electrophoresis units, mini-electrophoresis units, electrical transfer units, semi-dry electrical transfer unit, power supply units
Tissue dimembranator (tissue mill)
Hybridization oven, UV cross-linker DNA/RNA horizontal gel electrophoresis units
Cell culture incubators, bio-safety laminar flow hood
Refrigerated centrifuge, micro-centrifuges
Autoclave
Electrical balances, pH meters
-80 freezers, -20 freezer, refrigerator
Computer workstations

Current research projects include:

  • Cyclical finger loading: the effect of force and frequency on cyclical articular joint loading in vivo
  • Arthroplasty outcomes in diabetics: bone and cartilage metabolism
Research Associates

Bill Schroeder (present)

Laura Shum (past)

Marta Lishnevsky (past)

Ellen Roper (past)

Eric Etchill (past)

Graduate Students

Ph.D. students are accepted into this lab through the University of Colorado Denver’s Cell Biology, Stem Cells, and Development Graduate Program. 

Additional information on the graduate program is available at: http://medschool.ucdenver.edu/csd

Research Residents

R. Michael Ackerson, MD (2010-present)
Nuclear receptors in bone and cartilage metabolism

Trevor Oren, MD (2007 - 2010)
Arthroplasty in Veterans: analysis of cartilage, bone, serum and synovial fluid reveals differences and similarities in osteoarthritis with and without comorbid diabetes. Journal of Rehabilitation Research and Development. Accepted. 2011.

Post-doctoral Fellows

Marco Loayza, MD

Masters Students

Thomas Hraha
CU Bionegineering 

Medical Students

Amanda Munoz (2011 - present)
Bone and cartilage extracellular matrix metabolism in the diabetes environment

Andrew Berry (2011 - present)
Bone metabolism in genetic and other mouse models

Andrew DeMars (2009 - present)
AGE-RAGE in bone and cartilage: human and animal models with diabetes mellitus.

Chris Post (Summer, 2010)
Visiting from Wake Forest University School of Medicine

Keely Chevalier (2008 - 2009)
AGE-RAGE in a rat model for diabetes mellitus

Imran Choudhry (2007 - 2008)
Cytokines and low-back pain. Jointly supervised with Dr. M. Solomonow

Julian Ku (2008 -  2008)
Cytokines and low-back pain. Jointly supervised with Dr. M. Solomonow

Undergraduate Students

Eric Arriaga
Stanford University

Ananth Sridhar
Stanford University

HoanVu Nguyen
University of Colorado - Denver 

Fellows

Navid Ziran, MD (2007 - 2008)
The effect of age on in vivo bone formation by rat marrow stem cells. Jointly supervised with Dr. D. Hak

Research Student Interns - High School and Undergraduate

Brandon Martinez (Summer 2011 - Present)
Overland High School

Hannah Tighe (Spring, 2011)
CCTSI & Denver STARS Program, Denver East High School 

Terrance Bishop (Spring, 2011)
Denver School of Science and Technology

Fernanda Mora-Guitierrez (Winter, 2011; Summer, 2011)
Denver School of Science and Technology\

Andrew Jensen (Fall, 2010)
Denver School of Science and Technology

Eric Arriaga (Fall, 2009; Summer, 2011)
Denver School of Science and Technology

HoanVu Ngyuen (2008-2010)
Rangeview High School, Denver University

Ananth Sridar (Summer, 2007)
Stanford University

Hannah Reger
Denver East High School

BIBLIOGRAPHY:

Peer Reviewed

  1. KB King, S Chubinskaya, DL Reid, LH Madsen, and J Mollenhauer. Absence of cell-surface annexin V is accompanied by defective collagen matrix binding in the Swarm rat chondrosarcoma. Journal of Cellular Biochemistry. 65:131-144, 1997.
  2. J Mollenhauer, MT Mok, KB King, M Gupta, S Chubinskaya, H Koepp, and AA Cole.Expression of anchorin CII (cartilage annexin V) in human young, normal adult, and osteoarthritic cartilage. Journal of Histochemistry and Cytochemistry. 47:209-220, 1999.
  3. L Jennings, L Wu, KB King, H Hämmerle, G Cs-Szabo, and J Mollenhauer. The effects of collagen fragments on the extracellular matrix metabolism of bovine and human chondrocytes. Connective Tissue Research. 42:71-86, 2001.
  4. D Heinegård, K King, M Mörgelin, K Rosenberg, and C Wiberg. Matrix molecules with roles in cartilage assembly. In: Molecular Biology in Orthopaedics. RN Rosier and CH Evans, editors. American Academy of Orthopaedic Surgeons, Rosemont, IL, pp. 315-325, 2003.
  5. KB King and JH Kimura. The establishment and characterization of an immortal cell line with a stable chondrocytic phenotype. Journal of Cellular Biochemistry. 89:992-1004, 2003.
  6. A Mündermann, CO Derby, TP Andriacchi, and KB King.Serum concentration of cartilage oligomeric matrix protein (COMP) is sensitive to physiological cyclic loading in healthy adults. Osteoarthritis and Cartilage. 13:34-38, 2005.
  7. LH Nakama, KB King, SO Abrahamsson, and D Rempel.Evidence of microtears due to cyclical loading in an in vivo tendinopathy model. Journal of Orthopaedic Research. 23:1199-1205, 2005.
  8. LH Nakama, KB King, SO Abrahamsson, and D Rempel. VEGF, VEGFR-1, and CTGF cell densities in tendon are increased with cyclical loading: An in vivo tendinopathy model. Journal of Orthopaedic Research. 24:1-9, 2006.
  9. C Li, LA Pruitt, and KB King. Nanoindentation differentiates tissue-scale functional properties of native articular cartilage. Journal of Biomaterials Research. 17A:729-738, 2006.
  10. LH Nakama, KB King, S Abrahamsson, DM Rempel.Effect of Repetition Rate on the Formation of Microtears in Tendon in an In Vivo Cyclical Loading Model. Journal of Orthopaedic Research. 25:1176-1184. 2007.
  11. KR Asundi, KB King, and DM Rempel. Evaluation of gene expression through qRT-PCR in cyclically loaded tendons: an in vivo animal model. European Journal of Applied Physiology. 102:265-270, 2008.
  12. C Li, KB King, and LA Pruitt. Zone-specific changes in micromechanical, biochemical, and structural properties in articular cartilage from a rabbit joint flexion model. Materials Research Society Symposium Proceedings. 1097E:1-6, 2008.
  13. A Mündermann, KB King, RL Smith, and T Andriacchi. Change in serum COMP concentration due to ambulatory load is not related to knee OA status​. Journal of Orthopaedic Research. 27:1408-1413. 2009.
  14. K King, B Davidson, BH Zhou, Y Lu, and M Solomonow. High magnitude cyclic load triggers inflammatory response in lumbar ligaments. Clinical Biomechanics. 24:792-798. 2009.
  15. P D’Ambrosia, K King, B Davidson, BH Zhou, Y Lu, and M Solomonow. Pro-inflammatory cytokines increase following low and high magnitudes of cyclic loading of lumbar ligaments. European Spine Journal.  19:1330-1339. 2010.
  16. SE Pinski, KB King, BS Davidson, BH Zhou, Y Lu, and M Solomonow. High-frequency loading of lumbar ligaments increases proinflammatory cytokines expression in a feline model of repetitive musculoskeletal disorder. Spine Journal. 10:1078-1085, 2010.
  17. G Bilousova, DH Jun, KB King, S DeLanghe,WS Chick, EC Torchia, KS Chow, DJ Klemm, DR Roop, and SM Majka. Osteoblasts derived from induced pluripotent stem cells form calcified structures in scaffolds both in vitro and in vivo. Stem Cells. 29:206-16, 2011.
  18. TW Oren, S Botolin, A Williams, A Bucknell, and KB King. Arthroplasty in Veterans: analysis of cartilage, bone, serum and synovial fluid reveals differences and similarities in osteoarthritis with and without comorbid diabetes. Journal of Rehabilitation Research and Development. Accepted. 2011.

 

Book chapter

D Heinegård, K King, M Mörgelin, K Rosenberg, and C Wiberg. Matrix molecules with roles in cartilage assembly. In: Molecular Biology in Orthopaedics. RN Rosier and CH Evans, editors. American Academy of Orthopaedic Surgeons, Rosemont, IL, pp. 315-325, 2003.

 

Scientific abstracts

 

Peer-reviewed:

  1. MD Bushman, YA Gluzband, AJ Grodzinsky, KB King, JH Kimura, and KE Kuettner. Chondrocytes in agarose gel synthesize a mechanically functional matrix. Transactions Orthopaedic Research Society. 14:334-335, 1990.
  2. RJ Fernandes, KB King, JH Kimura, and TM Schmid. Swarm rat chondrosarcoma cell line synthesizes cartilage collagens in monolayer culture. Transactions Orthopaedic Research Society. 18:623, 1993.
  3. BB Böhm, B Wilbrink, KB King, KE Kuettner, and J Mollenhauer. Biochemical comparison of cartilage anchorin CII (annexin V) and muscle annexin V. Transactions Orthopaedic Research Society. 19:385, 1994.
  4. KB King, K Mikecz, JH Kimura, and J Mollenhauer. Absence of anchorin CII and impaired collagen binding in the Swarm rat chondrosarcoma. Transactions Orthopaedic Research Society.  20:387, 1995.
  5. JH Kimura, J Helenius, KB King, GJ Gibson, MB Schaffler, and AHK Plaas. Biosynthesis of aggrecan in a mutant cell line with a reduced intracellular sulfate precursor pool. Transactions Orthopaedic Research Society.  20:427, 1995.
  6. KB King, L Madsen, D Reid, S Chubinskaya, and J Mollenhauer. The absence of functional anchorin CII (cartilage annexin V) in the Swarm rat chondrosarcoma. Abstracts of the XVth Meeting of the Federation of the European Connective Tissue Societies. Munich, Germany, August 4-9, 1996, S8.
  7. J Mollenhauer, KB King, MT Mok, and H Hämmerle. The effect of degradation products from collagen type II on the collagen binding and metabolism of chondrocytes. Abstracts of the XVth Meeting of the Federation of the European Connective Tissue Societies. Munich, Germany, August 4-9, 1996, S14.
  8. KB King, P Lorenzo, MT Bayliss, and D Heinegård. Image analysis of molecular markers for osteoarthritis in human cartilage. Abstracts of the XVIth Meeting of the Federation of the European Connective Tissue Societies.  Uppsala, Sweden, August 1-6, 1998, K11.
  9. KB King, P Lorenzo, MT Bayliss, and D Heinegård. A definitive change occurs in the distribution of extracellular matrix molecules CILP and COMP in early-stage osteoarthritis. New Investigator’s Recognition Award semi-finalist. Transactions Orthopaedic Research Society.  45:303, 1999.
  10. K King and D Rempel. An animal model for tendinosis of the elbow (epicondylitis). Abstracts of the XVIIth Meeting of the Federation of the European Connective Tissue Societies. Patras, Greece, July 1-5, 2000, L6.
  11. KB King and DM Rempel. Cyclical loading in a rabbit finger flexor model produces structural changes in the elbow similar to tendinosis. ECM2000: International Conference on the Biology & Pathology of the Extracellular Matrix. St. Louis, MO, October 12-15, 2000, C63.
  12. D Rempel, K King, J Robertsson, LB Dahlin, and S Abrahmsson. An in vivo model for entrapment neuropathy due to repeated finger loading. Transactions Orthopaedic Research Society.  47:734, 2001.
  13. K King, D Mun, F Shao, E Diao, and D Rempel. Experimental induction of carpal tunnel syndrome: evaluation of tenosynovium. Transactions Orthopaedic Research Society.  48:870, 2002.
  14. N Gundiah, K Dao, K King, and L Pruitt. Determination of elastin and collagen content in porcine aorta. The IVth World Congress of Biomechanics in Calgary, Alberta. August 4-9, 2002.
  15. K King, L Nakama, A Reza, and D Rempel. Type III collagen in a model of elbow tendinosis. The 1st Meeting of the American Society for Matrix Biology, Houston, TX, November, 6-9, 2002, 99.
  16. DM Ebenstein, K King, and L Pruitt. A nanoindentation technique for measuring mechanical properties of finger joint cartilage. Transactions of the 29th Annual Meeting, Society for Biomaterials, Reno, NV, April 30 – May 3, p. 718, 2003.
  17. LA Pruitt, C Li, and KB King. Nanoindentation assessment of rabbit finger joint cartilage. 7th World Biomaterials Congress. 2004. Sydney, Australia
  18. C Li, DM Ebenstein, K King,  and LA Pruitt. Nanoindentation of finger joint cartilage in a fluid cell. Transactions Orthopaedic Research Society. 50:539, 2004.
  19. LH Nakama, KB King, and DM Rempel. The localization of vascular endothelial growth factor in a repetitively loaded tendon in vivo: an immunohistological study. Transactions Orthopaedic Research Society. 50:860, 2004.
  20. A Mündermann, KB King, CO Dyrby, and TP Andriacchi. Serum COMP concentration is related to load distribution at the knee during walking in healthy adults. The 28th Meeting of the American Society of Biomechanics, Sept. 8-11, 2004, Portland, OR.
  21. A Medellin, C Opel, and KB King. In vivo repetitive joint loading leads to uncalcified cartilage loss: Possible tidemark advancement. 8th International Conference on the Chemistry and Biology of Mineralized Tissues, October 17-22, 2004, Banff Centre, Alberta, Canada. 
  22. A Mündermann, KB King, CO Dyrby, and TP Andriacchi. Serum concentration of cartilage oligomeric matrix protein (COMP) is sensitive to a moderate walking exercise in healthy adults.  Transactions Orthopaedic Research Society. 51:1636, 2005.
  23. LH Nakama, KB King, and DM Rempel. The localization of connective tissue growth factor in cyclically loaded tendon at the epicondyle in an in vivo model of tendinosis.  Transactions Orthopaedic Research Society. 51:762, 2005.
  24. C Opel, D Rempel, and KB King. In vivo cyclical joint loading decreases unmineralized cartilage thickness in the rabbit metacarpophalangeal.  Transactions Orthopaedic Research Society. 51:1638, 2005.
  25. E Saadat, S. Majumdar, A. Burghardt, and KB King. Cyclical in vivo loading increases cartilage proteoglycan content in the rabbit metacarpophalangeal joint. Transactions Orthopaedic Research Society. 52:1352, 2006.
  26. GS Marecek, CF Opel, DM Rempel, and KB King. Repetitive finger joint flexion without external load leads to articular cartilage thinning in an in vivo rabbit model. Transactions Orthopaedic Research Society. 52:1898, 2006.
  27. LH Nakama, CC Wu, KB King, and DM Rempel. The effect of loading rate on VEGF, VEGFR-1 and CTGF production in an in vivo cyclically loaded tendon. Transactions Orthopaedic Research Society. 52:1095, 2006.
  28. LH Nakama, K Amano, KB King, and DM Rempel. Effect of repetition rate on blood vessel formation in the paratenon of a repetitively loaded tendon in vivo. Transactions Orthopaedic Research Society. 52:1096, 2006.
  29. C Li, K King, and L Pruitt. Depth-dependent nanomechanical response of soft biomaterials. Materials Research Society. San Francisco, CA, 2006.
  30. C Li, K King, and L Pruitt. Changes in biomechanical properties in articular cartilage due to cyclic loading. Annual Fall Meeting of the Biomedical Engineering Society. October 11-14, 2006. Chicago, IL. 714.
  31. C Li, KB King, DM Ebenstein, J. Lin, and L Pruitt. Analysis of force-displacement curves of cartilage and biomaterials. Transactions Orthopaedic Research Society. 53:1565, 2007.
  32. E Saadat, S. Majumdar, D. Rempel, and KB King. The effect of frequency and force of in vivo loading on proteoglycan content of rabbit articular cartilage. Transactions Orthopaedic Research Society. 54:50, 2008.
  33. C Li, KB King, and L Pruitt. Nanoindentation measurement in articular cartilage from an in vivo loading model. Transactions Orthopaedic Research Society. 54:649, 2008.
  34. C Li, KB King, and L Pruitt. Zone-specific changes in micromechanical, biochemical, and structural properties in articular cartilage from a rabbit joint flexion model. Materials Research Society Spring Meeting. San Francisco, March 25-28, 2008, GG1.10
  35. A. Mündermann, KB King, RL Smith, and T Andriacchi. Change in serum COMP concentration due to ambulatory load is not related to knee OA status. Transactions Orthopaedic Research Society. 55:1130, 2009.
  36. N Volmer, M Godek, KB King, and R Ayers. Effects of fuel ratio on the biomimitic properties of multiphasic calcium phosphate created via auto-ignition combustion synthesis. Society for Biomaterials Annual Meeting and Exposition, San Antonio, TX. April 22-25, 2009.
  37. KB King, T Jiang, XX Wang, and M Levi. The advanced glycation end product pentosidine is increased in the NZOcNON10 mouse model for type 2 diabetes. American Society for Bone and Mineral Research 31st Annual Meeting, Denver, CO. September 11-15, 2009.
  38. 38.  KB King, TW Findley, M Maney, AE Williams, and A Bucknell. Diabetics receive joint replacements more frequently and at a younger age. Transactions Orthopaedic Research Society. 56:409, 2010.
  39. 39.  KB King, AE Williams, T Oren and A Bucknell. Arthroplasty patients with diabetes mellitus have higher bone pentosidine levels and greater immunohistochemical RAGE and MMP-1 than patients without diabetes. American Society for Bone and Mineral Research 32nd Annual Meeting, Toronto, Ontario, October 15-19, 2010.
  40. J Wolf, KB King, and AE Williams. Serum relaxin is correlated with relaxin receptor expression and MMP-1 expression in the anterior oblique ligament. 66th Annual Meeting of the American Society for Surgery of the Hand, Las Vegas, NV, September 8-10, 2011.

 

Not peer-reviewed:

1.     C Opel, A Portnoy, and K King. Analysis of an animal model studying the mechanobiology of joint loading. University of California Systemwide Biomedical Engineering Symposium, San Diego, CA, June 22-23, 2003.

2.     KB King, C Lindsey, M Reis, L Steinbach, and S Majumdar. Serum COMP and cartilage volume. Arthritis Research Conference, Keystone, CO, June 26-29, 2003, P2.29.

3.     KB King. Effects of repetitive in vivo loading on articular joints. Arthritis Research Conference, Keystone, CO, June 26-29, 2003, P2.30.

4.     IK Choudhry, D Solomonow, E Roper, M Solomonow, and KB King. Cytokines in low back pain. 2008 Student Research Forum, University of Colorado, Denver, January 16, 2008.

5.     KM Chevallier, M Levi, Y Bogert, and KB King. RAGE expression in a rat model of diabetes: differential expression in diabetic vs. non-diabetic rat bone samples. 2009 Student Research Forum, University of Colorado, Denver, January 21, 2009.

R01 OH007786

P30  DK57516