Epidemiological studies have shown an association between hypertension and knee osteoarthritis (OA). The purpose of this study was to investigate whether activation of the renin–angiotensin system (RAS) can aggravate mechanical loading-induced knee OA in mice. Eight-week-old male Tsukuba hypertensive mice (THM) and C57BL/6 mice were divided into four groups: i) running THM group, ii) running C57BL/6 mice group, iii) non-running THM group, and iv) non-running C57BL/6 mice group. Mice in the running group were forced to run (25 m/min, 30 min/day, 5 days/week) on a treadmill. All mice in the four groups (n=10 in each group) were euthanized after 0, 2, 4, 6, or 8 weeks of running or natural breeding. Cartilage degeneration in the left knees was histologically evaluated using the modified Mankin score. Expression of Col X, MMP-13, angiotensin type 1 receptor (AT1R), and AT2R was examined immunohistochemically. To study the effects of stimulation of the AT1R in chondrocytes by mechanical loading and/or Angiotensin II (AngII) on transduction of intracellular signals, phosphorylation levels of JNK and Src were measured in bovine articular chondrocytes cultured in three-dimensional agarose scaffolds. After 4 weeks, the mean Mankin score for the lateral femoral condylar cartilage was significantly higher in the THM running group than in the C57BL/6 running group and non-running groups. AT1R and AT2R expression was not detected at 0 weeks in any group but was noted after 4 weeks in the THM running group. AT1R expression was also noted at 8 weeks in the C57BL/6 running group. The expression levels of AT1R, COL X, and MMP-13 in chondrocytes were significantly higher in the THM running group than in the control groups. Positive significant correlations were noted between the Mankin score and the rate of AT1R-immunopositive cells, between the rates of AT1R- and Col X-positive cells, and between the rates of AT1Rand AT2R-positive cells. The phosphorylation level of JNK was increased by cyclic compression loading or addition of AngII to the cultured chondrocytes and was reversed by pretreatment with an AT1R blocker. A synergistic effect on JNK phosphorylation was observed between compression loading and AngII addition. Transgene activation of renin and angiotensinogen aggravated mechanical load-induced knee OA in mice. These findings suggest that AT1R expression in chondrocytes is associated with early knee OA and plays a role in the progression of cartilage degeneration. The RAS may be a common molecular mechanism involved in the pathogenesis of hypertension and knee OA.

The lectin-like, oxidized low-density lipoprotein (ox-LDL) receptor-1 (LOX-1)/ox-LDL system contributes to atherosclerosis and may be involved in cartilage degeneration. The purpose of this study was to determine whether the LOX-1/ox-LDL system contributes to age-related osteoarthritis (OA) in vivo, using LOX-1 knockout (LOX-1 KO) mice. Knee cartilage from 6, 12, and 18-month old (n = 10/group) C57Bl/6 wild-type (WT) and LOX-1 KO mice was evaluated by determining the Osteoarthritis Research Society International (OARSI) score of Safranin-O stained samples. The prevalence of knee OA in both mouse strains was also investigated. Expression levels of LOX-1, ox-LDL, runt-related transcription factor-2 (Runx2), type-X collagen (COL X), and matrix metalloproteinase-13 (MMP-13) in the articular chondrocytes were analyzed immunohistologically. No significant difference was observed in the mean scores of WT (2.00±0.61) and LOX-1 KO mice (2.00±0.49) at 6 months of age (P=1.00, n=10). At 12 and 18 months of age, the mean scores of LOX-1 KO mice (3.75±0.93 and 5.50±0.78) were significantly lower than those of WT mice (5.25±1.14 and 9.00±1.01; P<0.001 in both cases; n=10). The prevalence of OA in LOX-1 KO mice was lower than that in WT mice at 12 and 18 months of age (40 vs 70%, 70 vs 90%, respectively; n=10). The expression levels of Runx2, COL X, and MMP-13 in articular chondrocytes significantly decreased in LOX-1 KO, mice compared with those in WT mice. The study indicated that the LOX-1/ox-LDL system in chondrocytes plays a role in the pathogenesis of age-related knee OA, which is potentially a target for preventing OA progression.

Angiotensin II type 1 receptor ( AT 1R) appears to have a mechanosensing function in a number of cell types. The purpose of this study was to examine whether AT 1R expressed in articular chondrocytes is involved in osteoarthritis (OA) progression in vivo and whether cyclic compressive loading activates the AT 1R and stimulates hypertrophic differentiation of chondrocytes in vitro . The relationships between the modified Mankin score for cartilage degeneration and the expression of AT 1R and type X collagen (Col X) were studied in mouse knees with OA induced using the destabilization‐of‐medial‐meniscus model. Cyclic compressive loads were applied to cultured bovine articular chondrocytes in three‐dimensional agarose scaffolds. Expression of Col X and runt‐related transcription factor 2 (Runx2) was analyzed using RT‐PCR and western blotting. We dissected the downstream pathway for intracellular signal transductions of AT 1R including G‐protein‐dependent and G‐protein‐independent pathways. Positive significant correlations between the Mankin score and the rate of AT 1R‐immunopositive cells and between the rates of AT 1R and Col X expression were noted. The expression of Col X and Runx2 was increased by compressive loading but suppressed by addition of olmesartan, an Ang II receptor blocker, to the agarose scaffolds. Compressive loading upregulated the phosphorylation of c‐Jun N‐terminal kinase ( JNK ), Src, and STAT 1, but olmesartan significantly suppressed only JNK phosphorylation. We conclude that AT 1R expressed by articular chondrocytes may be involved in OA progression in vivo . Mechanical stress can activate AT 1R and stimulate hypertrophic differentiation of chondrocytes through the G‐protein‐dependent pathway. AT 1R has a mechanosensing function in chondrocytes and may be a new therapeutic target in OA .

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Purpose: We design a study to elucidate the precise molecular mechanisms by which Sorbitol-modified hyaluronic acid (sorbitol/HA) exerts beneficial effects in osteoarthritis (OA). Methods: Human OA chondrocytes were treated with increasing doses of sorbitol/HA and thereafter with or without interleukin-1beta (IL-1b) or hydrogen peroxide (H 2 O 2). Signal transduction pathways and parameters related to oxidative stress, apoptosis, inflammation, and catabolism were investigated. Results: Sorbitol/HA prevented IL-1 b-induced oxidative stress, as