Regulation of Articular Cartilage Proteoglycan 4 Secretion in Aging and Osteoarthritis

Proteoglycan 4 (PRG4) is a macromolecule synthesized and found within the synovial joint that contributes lubricating and other functions to maintain joint health. PRG4 secretion by articular cartilage is an important parameter of PRG4 mass balance in the synovial joint and is influenced in vitro by a number of chemical and mechanical mediators. With joint aging and osteoarthritis (OA), cartilage PRG4 secretion may be altered due to changes in constitutive and induced chondrocyte expression and changes in SF regulation of cartilage. The overall motivation of this dissertation was to contribute to an understanding of the changes in regulation of articular cartilage PRG4 secretion by TGF-β1, a potent stimulus, and by human synovial fluid (hSF), a complex mixture that interacts with cartilage physiologically, with aging and OA.

In normal human articular cartilage, constitutive and TGF-β1-stimulated PRG4 production decreased with increasing age, and these age-dependent declines were associated with decreases with age in the number of PRG4+ chondrocytes without a marked alteration in the density of chondrocytes in the superficial zone. Changes in activity and responsiveness of chondrocytes likely underlie age-related declines in PRG4 production. Age-associated decrease in cartilage constitutive and TGF-β1- stimulated PRG4 production may be related to the age-associated predisposition to cartilage degeneration and OA. hSF contains endogenous regulators of cartilage PRG4 secretion, resulting in a net stimulation. Cartilage PRG4 secretion was substantially stimulated by hSF from OA patients (OA-hSF), compared to hSF from normal cadaveric donors (NL-hSF) and pooled human serum (HS) from normal adult donors. OA-hSF stimulation of cartilage PRG4 secretion was not substantially modulated by inhibition of the TGF-β, IL-1, and/or TNF signaling pathways, individually.

Elucidating the age- and OA- related changes in cartilage PRG4 secretion, due to alterations in constitutive and induced chondrocyte expression and alterations in hSF regulation of cartilage, is one step towards a systems-based understanding of synovial joint PRG4 homeostasis and derangement in health, aging, and disease.

Year	Entry
2002	McGowan KB, Kurtis MS, Lottman LM, Watson D, Sah RL. Biochemical quantification of DNA in human articular and septal cartilage using PicoGreen^® and Hoechst 33258. Osteoarthritis Cartilage. July 2002;10(7):580-587.
1961	Outerbridge RE. The etiology of chondromalacia patellae. J Bone Joint Surg. November 1961;43B(4):752-757.
2003	Klein TJ, Schumacher BL, Schmidt TA, Li KW, Voegtline MS, Masuda K, Thonar EJ-MA, Sah RL. Tissue engineering of stratified articular cartilage from chondrocyte subpopulations. Osteoarthritis Cartilage. August 2003;11(8):595-602.
2008	Elsaid KA, Fleming BC, Oksendahl HL, Machan JT, Fadale PD, Hulstyn MJ, Shalvoy R, Jay GD. Decreased lubricin concentrations and markers of joint inflammation in synovial fluids from patients with anterior cruciate ligament injury. Arthritis Rheum. June 2008;58(6):1707-1715.
2007	Khalafi A, Schmid TM, Neu C, Reddi AH. Increased accumulation of superficial zone protein (SZP) in articular cartilage in response to bone morphogenetic protein-7 and growth factors. J Orthop Res. March 2007;25(3):293-303.
2005	Ateshian GA, Mow VC. Friction, lubrication, and wear of articular cartilage and diarthrodial joints. In: Mow VC, Huiskes R, eds. Basic Orthopaedic Biomechanics & Mechano-Biology. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:447-494.
1953	Ogston AG, Stanier JE. The physiological function of hyaluronic acid in synovial fluid: viscous, elastic and lubricant properties. J Physiol. 1953;119(2-3):244-252.
1994	Schumacher BL, Block JA, Schmid TM, Aydelotte MB, Kuettner KE. A novel proteoglycan synthesized and secreted by chondrocytes of the superficial zone of articular cartilage. Arch Biochem Biophys. May 1994;311(1):144-152.
2007	Schmidt TA, Gastelum NS, Nguyen QT, Schumacher BL, Sah RL. Boundary lubrication of articular cartilage: role of synovial fluid constituents. Arthritis Rheum. March 2007;56(3):882-891.
1999	Flannery CR, Hughes CE, Schumacher BL, Tudor D, Aydelotte MB, Kuettner KE, Caterson B. Articular cartilage superficial zone protein (SZP) is homologous to megakaryocyte stimulating factor precursor and is a multifunctional proteoglycan with potential growth-promoting, cytoprotective, and lubricating properties in cartilage metabolism. Biochem Biophys Res Commun. January 27, 1999;254(3):535-541.
2010	Lotz MK. Posttraumatic osteoarthritis: pathogenesis and pharmacological treatment options. Arthritis Res Ther. 2010;12:211.
2005	Mow VC, Huiskes R, eds. Basic Orthopaedic Biomechanics & Mechano-Biology. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.
1981	Swann DA, Slayter HS, Silver FH. The molecular structure of lubricating glycoprotein-i, the boundary lubricant for articular cartilage. J Biol Chem. June 10, 1981;256(11):5921-5925.
2007	Jay GD, Torres JR, Rhee DK, Helminen HJ, Hytinnen MM, Cha C-J, Elsaid K, Kim K-S, Cui Y, Warman ML. Association between friction and wear in diarthrodial joints lacking lubricin. Arthritis Rheum. November 2007;56(11):3662-3669.
2001	Jay GD, Tantravahi U, Britt DE, Barrach HJ, Cha C-J. Homology of lubricin and superficial zone protein (SZP): products of megakaryocyte stimulating factor (MSF) gene expression by human synovial fibroblasts and articular chondrocytes localized to chromosome 1q25. J Orthop Res. July 2001;19(4):677-687.
2010	Sellam J, Berenbaum F. The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis. Nat Rev Rheumatol. November 2010;6(11):625-635.
2011	Anderson DD, Chubinskaya S, Guilak F, Martin JA, Oegema TR, Olson SA, Buckwalter JA. Post-traumatic osteoarthritis: improved understanding and opportunities for early intervention. J Orthop Res. June 2011;29(6):802-809.
1999	Schumacher BL, Hughes CE, Kuettner KE, Caterson B, Aydelotte MB. Immunodetection and partial cDNA sequence of the proteoglycan, superficial zone protein, synthesized by cells lining synovial joints. J Orthop Res. January 1999;17(1):110-120.

Year

Entry

2002

McGowan KB, Kurtis MS, Lottman LM, Watson D, Sah RL. Biochemical quantification of DNA in human articular and septal cartilage using PicoGreen^® and Hoechst 33258. Osteoarthritis Cartilage. July 2002;10(7):580-587.

1961

Outerbridge RE. The etiology of chondromalacia patellae. J Bone Joint Surg. November 1961;43B(4):752-757.

2003

Klein TJ, Schumacher BL, Schmidt TA, Li KW, Voegtline MS, Masuda K, Thonar EJ-MA, Sah RL. Tissue engineering of stratified articular cartilage from chondrocyte subpopulations. Osteoarthritis Cartilage. August 2003;11(8):595-602.

2008

Elsaid KA, Fleming BC, Oksendahl HL, Machan JT, Fadale PD, Hulstyn MJ, Shalvoy R, Jay GD. Decreased lubricin concentrations and markers of joint inflammation in synovial fluids from patients with anterior cruciate ligament injury. Arthritis Rheum. June 2008;58(6):1707-1715.

2007

Khalafi A, Schmid TM, Neu C, Reddi AH. Increased accumulation of superficial zone protein (SZP) in articular cartilage in response to bone morphogenetic protein-7 and growth factors. J Orthop Res. March 2007;25(3):293-303.

2005

Ateshian GA, Mow VC. Friction, lubrication, and wear of articular cartilage and diarthrodial joints. In: Mow VC, Huiskes R, eds. Basic Orthopaedic Biomechanics & Mechano-Biology. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:447-494.

1953

Ogston AG, Stanier JE. The physiological function of hyaluronic acid in synovial fluid: viscous, elastic and lubricant properties. J Physiol. 1953;119(2-3):244-252.

1994

Schumacher BL, Block JA, Schmid TM, Aydelotte MB, Kuettner KE. A novel proteoglycan synthesized and secreted by chondrocytes of the superficial zone of articular cartilage. Arch Biochem Biophys. May 1994;311(1):144-152.

2007

Schmidt TA, Gastelum NS, Nguyen QT, Schumacher BL, Sah RL. Boundary lubrication of articular cartilage: role of synovial fluid constituents. Arthritis Rheum. March 2007;56(3):882-891.

1999

Flannery CR, Hughes CE, Schumacher BL, Tudor D, Aydelotte MB, Kuettner KE, Caterson B. Articular cartilage superficial zone protein (SZP) is homologous to megakaryocyte stimulating factor precursor and is a multifunctional proteoglycan with potential growth-promoting, cytoprotective, and lubricating properties in cartilage metabolism. Biochem Biophys Res Commun. January 27, 1999;254(3):535-541.

2010

Lotz MK. Posttraumatic osteoarthritis: pathogenesis and pharmacological treatment options. Arthritis Res Ther. 2010;12:211.

2005

Mow VC, Huiskes R, eds. Basic Orthopaedic Biomechanics & Mechano-Biology. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.

1981

Swann DA, Slayter HS, Silver FH. The molecular structure of lubricating glycoprotein-i, the boundary lubricant for articular cartilage. J Biol Chem. June 10, 1981;256(11):5921-5925.

2007

Jay GD, Torres JR, Rhee DK, Helminen HJ, Hytinnen MM, Cha C-J, Elsaid K, Kim K-S, Cui Y, Warman ML. Association between friction and wear in diarthrodial joints lacking lubricin. Arthritis Rheum. November 2007;56(11):3662-3669.

2001

Jay GD, Tantravahi U, Britt DE, Barrach HJ, Cha C-J. Homology of lubricin and superficial zone protein (SZP): products of megakaryocyte stimulating factor (MSF) gene expression by human synovial fibroblasts and articular chondrocytes localized to chromosome 1q25. J Orthop Res. July 2001;19(4):677-687.

2010

Sellam J, Berenbaum F. The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis. Nat Rev Rheumatol. November 2010;6(11):625-635.

2011

Anderson DD, Chubinskaya S, Guilak F, Martin JA, Oegema TR, Olson SA, Buckwalter JA. Post-traumatic osteoarthritis: improved understanding and opportunities for early intervention. J Orthop Res. June 2011;29(6):802-809.

1999

Schumacher BL, Hughes CE, Kuettner KE, Caterson B, Aydelotte MB. Immunodetection and partial cDNA sequence of the proteoglycan, superficial zone protein, synthesized by cells lining synovial joints. J Orthop Res. January 1999;17(1):110-120.

Year	Entry
2020	Matheson AR. Proteoglycan-4 in Equine Joint Disease, Exercise, and in Vitro Cartilage Repair [PhD thesis]. Calgary, AB: University of Calgary; May 2020.

Year

Entry

2020

Matheson AR. Proteoglycan-4 in Equine Joint Disease, Exercise, and in Vitro Cartilage Repair [PhD thesis]. Calgary, AB: University of Calgary; May 2020.