Differential effects of aging on human chondrocyte responses to transforming growth factor β. Increased pyrophosphate production and decreased cell proliferation

Rosen, Fred; McCabe, G; Quach, Jacqueline; Solan, Joell L.; Terkeltaub, Robert; Seegmiller, J. Edwin; Lotz, Martin

doi:10.1002/art.1780400712

Cited by 14 publications

(19 citation statements)

References 34 publications

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“…14 In addition to its effect on osteophytosis, transforming growth factor β1 enhances production of extracellular pyrophosphate by chondrocytes, 30 and mechanical perturbation of chondrocytes increases the release of ATP, a potent source of extracellular pyrophosphate, 31 thereby predisposing to pyrophosphate crystal formation. Such shared chemical and/or mechanical predisposing factors may explain the association between osteophytosis and chondrocalcinosis seen in this study.…”

Section: Discussionmentioning

confidence: 99%

Characterisation of size and direction of osteophyte in knee osteoarthritis: a radiographic study

Nagaosa

2002

Annals of the Rheumatic Diseases

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Objectives: To examine the size and direction of osteophyte in knee osteoarthritis (OA) and to determine associations between osteophyte size and other radiographic features. Methods: Knee radiographs (standing extended anteroposterior and 30 degrees flexion skyline views) were examined from 204 patients referred to hospital with symptomatic knee OA (155 women, 49 men; mean age 70, range 34-91 years). A single observer assessed films for osteophyte size and direction at eight sites; narrowing in each compartment; varus/valgus angulation; patellofemoral subluxation; attrition; and chondrocalcinosis using a standard atlas, direct measurement, or visual assessment. For analysis, one OA knee was selected at random from each subject. Results: Osteophyte direction at the eight sites was divisible into five categories. At all sites, except for the lateral tibial plateau and the medial patella, osteophyte direction varied according to (a) the size of osteophyte and (b) the degree of local narrowing. At the medial femur, medial tibia, and lateral femur osteophyte direction changed from being predominantly horizontal to predominantly vertical with increasing size. The size of osteophyte correlated positively with the severity of local narrowing, except for the medial patellofemoral compartment where osteophyte size correlated positively with the severity of narrowing in the medial tibiofemoral compartment. Logistic regression analysis showed that osteophyte size was associated not only with local narrowing but also with local malalignment and bone attrition, and that chondrocalcinosis was positively associated with osteophyte size at multiple sites. Conclusion: In patients referred to hospital with knee OA different patterns of osteophyte direction are discernible. Osteophyte size is associated with local compartmental narrowing but also local alignment and attrition. Chondrocalcinosis is associated with osteophytosis throughout the joint. These data suggest that both local biomechanical and constitutional factors influence the size and direction of osteophyte formation in knee OA.

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Section: Discussionmentioning

confidence: 99%

Characterisation of size and direction of osteophyte in knee osteoarthritis: a radiographic study

Nagaosa

2002

Annals of the Rheumatic Diseases

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“…Important changes occur in chondrocyte production of pyrophosphate with aging. The levels of constitu- tively produced and TGF-␤-induced pyrophosphate increase with aging in articular chondrocytes (31,32). Thus, with advancing age there are several changes that represent potential risk factors for the development of osteoarthritis.…”

Section: Fig 3 (A) Ntpph and Alkaline Phosphatase Activity Apoptotmentioning

confidence: 99%

Chondrocyte-derived apoptotic bodies and calcification of articular cartilage

Hashimoto

Ochs

Rosen

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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257

206

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Chondrocytes exposed to nitric oxide (NO) or antibody to Fas undergo cell death by apoptosis. This study examines structural and functional properties of chondrocyte-derived apoptotic bodies. In NO treated cartilage, the dense pericellular matrix that normally surrounds the cells is degraded and apoptotic bodies accumulate within and in the vicinity of the chondrocyte lacunae. Functional analysis shows that apoptotic bodies isolated from NO-treated chondrocytes or cartilage produce pyrophosphate. The levels of pyrophosphate produced by apoptotic bodies are increased by pretreatment of the chondrocytes with transforming growth factor ␤ and decreased by interleukin 1. Apoptotic bodies contain alkaline phosphatase and NTP pyrophosphohydrolase activities and can precipitate calcium. These results suggest that chondrocyte-derived apoptotic bodies express functional properties that may contribute to the pathologic cartilage calcification observed in aging and osteoarthritis.

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“…Characterization of human [2,13], equine [21], bovine [1,7,11,35], rabbit [34] and mouse [25] cultured articular cartilage explants revealed that intrinsic metabolism of chondrocytes and their response to external factors vary with animal age. It has also been shown that chondrocytes isolated from cartilage behave in an age-dependent manner, although many of these studies involved monolayer culture [8,27,29,32,33], which induces dedifferentiation of chondrocytes towards a more fibroblastic-like phenotype.…”

Section: Introductionmentioning

confidence: 99%

Aged bovine chondrocytes display a diminished capacity to produce a collagen-rich, mechanically functional cartilage extracellular matrix

et al. 2005

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Most fundamental studies in cartilage tissue engineering investigate the ability of chondrocytes from young animals to produce cartilaginous matrix under various conditions, while current clinical applications such as autologous chondrocyte implantation, use chondrocytes from donors that are decades past skeletal maturity. Previous investigations have suggested that several characteristics of primary chondrocytes are age-dependent but none have quantified cell proliferation, proteoglycan synthesis and accumulation, collagen synthesis and accumulation, compressive and tensile mechanical properties in order to examine the effects of donor age on all of these parameters. We enzymatically isolated primary bovine chondrocytes from fetal, young and aged animals and cultured these cells in agarose gels to assess the above-mentioned properties. We found that fetal and young (but still skeletally mature i.e. 18-month-old bovine) chondrocytes behaved similarly, while aged chondrocytes (5-to 7-year-old bovine) displayed diminished proliferation (-2x less), a slightly reduced proteoglycan accumulation per cell (-20%), and significantly less collagen accumulation per cell (-55%) compared to the younger cells. Histological observations and mechanical properties supported these findings, where a particularly significant reduction in tensile stiffness produced by aged chondrocytes compared to younger cells was observed. Our findings suggest that donor age is an important factor in determining the outcome and potential success when tissue-engineered cartilage is produced from articular chondrocytes. More specifically, primary chondrocytes from aged donors may not possess sufficient capacity to produce the extracellular matrix that is required for a mechanically resilient tissue.

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Differential effects of aging on human chondrocyte responses to transforming growth factor β. Increased pyrophosphate production and decreased cell proliferation

Cited by 14 publications

References 34 publications

Characterisation of size and direction of osteophyte in knee osteoarthritis: a radiographic study

Characterisation of size and direction of osteophyte in knee osteoarthritis: a radiographic study

Chondrocyte-derived apoptotic bodies and calcification of articular cartilage

Aged bovine chondrocytes display a diminished capacity to produce a collagen-rich, mechanically functional cartilage extracellular matrix

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