Osteoarthritic changes in vervet monkey knees correlate with meniscus degradation and increased matrix metalloproteinase and cytokine secretion.

OBJECTIVE Meniscus injury increases osteoarthritis risk but its pathobiology in osteoarthritis is unclear. We hypothesized that older adult vervet monkeys would exhibit knee osteoarthritic changes and the degenerative menisci from these animals would secrete matrix metalloproteinases (MMPs) and pro-inflammatory cytokines that contribute to the development of osteoarthritis. DESIGN In a cross sectional analysis of healthy young adult (9-12 years) and old (19-26 years) adult female vervet monkeys, knees were evaluated in vivo with computed tomography (CT) imaging, and joint tissues were morphologically graded at necropsy. Meniscus explants were subsequently cultured to evaluate meniscal MMP and cytokine secretion. RESULTS CT images revealed significant bony osteoarthritic changes in 80% of older monkeys which included increases in osteophyte number and meniscal calcification. Meniscus and cartilage degradation scores were greater in the older monkeys and were positively correlated (r > 0.7). Menisci from older animals exhibiting osteoarthritic changes secreted significantly more MMP-1, MMP-3, and MMP-8 than healthy menisci from younger monkeys. Older menisci without significant osteoarthritic changes secreted more IL-7 than healthy young menisci while older osteoarthritic menisci secreted more IL-7 and granulocyte-macrophage colony-stimulating factor than healthy older menisci. CONCLUSIONS Aged vervets develop naturally occurring knee osteoarthritis that includes involvement of the meniscus. Degenerative menisci secreted markedly increased amounts of matrix-degrading enzymes and inflammatory cytokines. These factors would be expected to act on the meniscus tissue and local joint tissues and may ultimately promote osteoarthritis development. These finding also suggest vervet monkeys are a useful animal model for studying the progression of osteoarthritis.

[1]  B. Lindgren,et al.  Effects of long-term estrogen replacement therapy on osteoarthritis severity in cynomolgus monkeys. , 2002, Arthritis and rheumatism.

[2]  T. Kojima,et al.  Roles of metalloproteinase-3 and aggrecanase 1 and 2 in aggrecan cleavage during human meniscus degeneration , 2009, Orthopedic reviews.

[3]  C. Shively,et al.  The unique value of primate models in translational research , 2009, American journal of primatology.

[4]  K. Pritzker,et al.  Spontaneous osteoarthritis in rhesus macaques. I. Chemical and biochemical studies. , 1989, The Journal of rheumatology.

[5]  P. Babyn,et al.  Osteoarthritis staging: comparison between magnetic resonance imaging, gross pathology and histopathology in the rhesus macaque. , 1995, Osteoarthritis and cartilage.

[6]  L. Sharma,et al.  Risk factors for medial meniscal pathology on knee MRI in older US adults: a multicentre prospective cohort study , 2011, Annals of the rheumatic diseases.

[7]  F. Eckstein,et al.  The association of prevalent medial meniscal pathology with cartilage loss in the medial tibiofemoral compartment over a 2-year period. , 2010, Osteoarthritis and cartilage.

[8]  E. Fuller,et al.  Zonal differences in meniscus matrix turnover and cytokine response. , 2012, Osteoarthritis and cartilage.

[9]  G. Panayi,et al.  Cytokine expression in synovial membranes of patients with rheumatoid arthritis and osteoarthritis. , 1993, Annals of the rheumatic diseases.

[10]  Steven J Schapiro,et al.  Use of primates in research: A global overview , 2004, American journal of primatology.

[11]  Kyriacos A Athanasiou,et al.  The knee meniscus: structure-function, pathophysiology, current repair techniques, and prospects for regeneration. , 2011, Biomaterials.

[12]  R. Loeser,et al.  Pro-inflammatory stimulation of meniscus cells increases production of matrix metalloproteinases and additional catabolic factors involved in osteoarthritis pathogenesis. , 2014, Osteoarthritis and cartilage.

[13]  K. Frosch,et al.  Interleukin-7 levels in synovial fluid increase with age and MMP-1 levels decrease with progression of osteoarthritis , 2012, Acta orthopaedica.

[14]  R. Jakob,et al.  Long-term Results of Arthroscopic Meniscal Repair , 1995, The American journal of sports medicine.

[15]  S. Kritchevsky,et al.  Force-generation capacity of single vastus lateralis muscle fibers and physical function decline with age in African green vervet monkeys. , 2013, The journals of gerontology. Series A, Biological sciences and medical sciences.

[16]  S. Davies,et al.  Exuberant expression of chemokine genes by adult human articular chondrocytes in response to IL-1beta. , 2008, Osteoarthritis and cartilage.

[17]  F. Guilak,et al.  The Effects of Adipokines on Cartilage and Meniscus Catabolism , 2011, Connective tissue research.

[18]  P A Dieppe,et al.  Magnetic resonance imaging in osteoarthritis of the knee: correlation with radiographic and scintigraphic findings. , 1991, Annals of the rheumatic diseases.

[19]  S. Goldring,et al.  Osteoarthritis: a disease of the joint as an organ. , 2012, Arthritis and rheumatism.

[20]  K. Pritzker,et al.  Spontaneous osteoarthritis in rhesus macaques. II. Characterization of disease and morphometric studies. , 1990, The Journal of rheumatology.

[21]  L. Fairbanks,et al.  Age, reproductive value, and dominance-related behaviour in vervet monkey females: cross-generational influences on social relationships and reproduction , 1986, Animal Behaviour.

[22]  Ali Guermazi,et al.  The role of the meniscus in knee osteoarthritis: a cause or consequence? , 2009, Radiologic clinics of North America.

[23]  R. Rawlins,et al.  Aging in the musculoskeletal system of rhesus monkeys: I. Passive joint excursion. , 1983, American journal of physical anthropology.

[24]  R. Jurmain.  Degenerative joint disease in African great apes: an evolutionary perspective. , 2000, Journal of human evolution.

[25]  Ali Guermazi,et al.  Meniscal tear in knees without surgery and the development of radiographic osteoarthritis among middle-aged and elderly persons: The Multicenter Osteoarthritis Study. , 2009, Arthritis and rheumatism.

[26]  C J DeRousseau,et al.  Aging in the musculoskeletal system of rhesus monkeys: II. Degenerative joint disease. , 1985, American journal of physical anthropology.

[27]  T. Stein,et al.  Long-Term Outcome After Arthroscopic Meniscal Repair Versus Arthroscopic Partial Meniscectomy for Traumatic Meniscal Tears , 2010, The American journal of sports medicine.

[28]  R. Loeser,et al.  Human articular chondrocytes produce IL-7 and respond to IL-7 with increased production of matrix metalloproteinase-13 , 2008, Arthritis research & therapy.

[29]  R. Brophy,et al.  Molecular analysis of age and sex-related gene expression in meniscal tears with and without a concomitant anterior cruciate ligament tear. , 2012, The Journal of bone and joint surgery. American volume.

[30]  E. Roos,et al.  The Long-term Consequence of Anterior Cruciate Ligament and Meniscus Injuries , 2007, The American journal of sports medicine.

[31]  K. Pritzker,et al.  Rhesus macaques as an experimental model for degenerative arthritis. , 1989, Puerto Rico health sciences journal.

[32]  B. Bresnihan,et al.  Synovial tissue inflammation in early and late osteoarthritis , 2005, Annals of the rheumatic diseases.

[33]  D. Patra,et al.  Transcriptome analysis of injured human meniscus reveals a distinct phenotype of meniscus degeneration with aging. , 2013, Arthritis and rheumatism.

[34]  Linda Troeberg,et al.  Proteases involved in cartilage matrix degradation in osteoarthritis. , 2012, Biochimica et biophysica acta.

[35]  M. Goldring,et al.  Inflammation in osteoarthritis , 2011, Current opinion in rheumatology.

[36]  A Guermazi,et al.  The association of meniscal pathologic changes with cartilage loss in symptomatic knee osteoarthritis. , 2006, Arthritis and rheumatism.

[37]  Farshid Guilak,et al.  Inhibition of Matrix Metalloproteinases Enhances In Vitro Repair of the Meniscus , 2009, Clinical orthopaedics and related research.

[38]  Aging and physical mobility in group-housed Old World monkeys , 2012, AGE.

[39]  Tan Zhang,et al.  Myosin heavy chain isoform expression in the Vastus Lateralis muscle of aging African green vervet monkeys , 2012, Experimental Gerontology.

[40]  R. Loeser,et al.  Osteoarthritis in cynomolgus macaques III: Effects of age, gender, and subchondral bone thickness on the severity of disease , 1996, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[41]  Yubo Sun,et al.  Analysis of meniscal degeneration and meniscal gene expression , 2010 .

[42]  Farshid Guilak,et al.  Synovial fluid concentrations and relative potency of interleukin‐1 alpha and beta in cartilage and meniscus degradation , 2013, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[43]  D. Nicolella,et al.  Reproductive status and sex show strong effects on knee OA in a baboon model. , 2013, Osteoarthritis and cartilage.

[44]  F. Luyten,et al.  A homeostatic function of CXCR2 signalling in articular cartilage , 2014, Annals of the rheumatic diseases.

[45]  Thomas L. Smith,et al.  Age-related degenerative functional, radiographic, and histological changes of the shoulder in nonhuman primates. , 2013, Journal of shoulder and elbow surgery.