Catabolic stress induces features of chondrocyte senescence through overexpression of caveolin 1: Possible involvement of caveolin 1–induced down‐regulation of articular chondrocytes in the pathogenesis of osteoarthritis

Abstract

Objective. Articular chondrocyte senescence is responsible, at least in part, for the increased incidence of osteoarthritis (OA) with increased age. Recently, it was suggested that caveolin 1, a 21-24-kd membrane protein, participates in premature cellular senescence. Caveolin 1 is the principal structural component of caveolae, vesicular invaginations of the plasma membrane. This study was undertaken to investigate whether the catabolic factors oxidative stress and interleukin-1␤ (IL-1␤) induce features of premature senescence of articular chondrocytes through up-regulation of caveolin 1 expression.Methods. Caveolin 1 expression was investigated in human OA cartilage by real-time polymerase chain reaction and in rat OA cartilage by immunohistologic analysis. We studied whether IL-1␤ and H 2 O 2 induce caveolin 1 expression in OA chondrocytes and analyzed the relationship between cellular senescent phenotypes and caveolin 1 expression in human chondrocytes.Results. In human and rat OA articular cartilage, caveolin 1 positivity was associated with cartilage degeneration. Both IL-1␤ and H 2 O 2 up-regulated caveolin 1 messenger RNA and protein levels, and both treatments induced marked expression of senescent phenotypes: altered cellular morphology, cell growth arrest, telomere erosion, and specific senescence-associated ␤-galactosidase activity. Caveolin 1 overexpression induced p38 MAPK activation and impaired the ability of chondrocytes to produce type II collagen and aggrecan. Articular cartilage stability depends on the biosynthetic activities of chondrocytes, which counteract normal degradation of matrix macromolecules. Aging and the degeneration of articular cartilage in osteoarthritis (OA) are distinct processes; however, the incidence and prevalence of synovial joint degeneration increase dramatically in middle age (1) and the risk of posttraumatic OA following intraarticular fracture of

Water‐soluble C60 fullerene prevents degeneration of articular cartilage in osteoarthritis via down‐regulation of chondrocyte catabolic activity and inhibition of cartilage degeneration during disease development

“…It is well known that chondrocytes can adapt to hypoxic conditions, since articular cartilage is an avascular tissue (10,19). Thus, chondrocyte activity was studied under hypoxic, as well as normoxic, culture conditions in vitro.…”

“…Chondrocyte apoptosis was detected using an apoptosis detection kit (terminal deoxynucleotidyl transferase [TdT] in situ apoptosis detection kit; R&D Systems) in chondrocyte cell cultures, in accordance with the manufacturer's protocol. The kit was used to identify apoptotic chondrocytes by detecting DNA fragmentation through a combination of enzymology and immunohistochemistry techniques (19). Biotinylated nucleotides are incorporated into the 3Ј-OH ends of the DNA fragments by TdT.…”

“…There is a general consensus that a strong association exists between age and the incidence and prevalence of OA (8,(14)(15)(16)(17)(18)(19). Martin et al demonstrated that aging decreases the ability of chondrocytes to maintain and repair articular cartilage (15,16).…”

“…Recent reports also revealed that chondrocyte aging is closely involved in oxidative stress, such as the induction of ROS by extrinsic stress (e.g., mechanical force) in degenerated articular cartilage (11)(12)(13)19,23). It has been reported that oxygen-derived free radicals directly damage the guanine repeats in the telomere DNA (24)(25)(26)(27).…”

Heme oxygenase-1 induction modulates microsomal prostaglandin E synthase-1 expression and prostaglandin E2 production in osteoarthritic chondrocytes

“…Furthermore, studies examining the life span of articular chondrocytes have demonstrated that oxidative stress is related to premature senescence and may be responsible for the development of OA [8,9].…”