Activation of the renin-angiotensin system in mice aggravates mechanical loading-induced knee osteoarthritis

Abstract

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.

Long Non-Coding RNA (lncRNA) Small Nucleolar RNA Host Gene 15 (SNHG15) Alleviates Osteoarthritis Progression by Regulation of Extracellular Matrix Homeostasis

“…Afterwards, the sections were hydrated with a series of ethanol, followed by staining with hematoxylin for 1 min, 0.02% fast green for 5 min, and 0.1% Safranin-O for 30 min. The severity of OA articular cartilage degeneration was evaluated using the OARSI scores and modified Mankin scales [ 31 , 32 ]. For immunohistochemistry assay, paraffin-embedded tissue sections were dewaxed to water and incubated with primary antibodies including anti-COL2A1 (ab34712, Abcam) and anti-Aggrecan (13880-1-AP, ProteinTech) at 4°C overnight, followed by biotin-labeled secondary antibodies at 37°C for 15 min.…”

The role of oxidation of low-density lipids in pathogenesis of osteoarthritis: A narrative review

“…65 Furthermore, we found that the Tsukuba spontaneous hypertension mouse model had more severe OA than controlled wild type mice in the forced running model. 66 These findings indicate that the RAS is involved in the pathogenesis of OA. Activation of LOX-1 contributes as a mediator of the RAS system.…”

A journal of histochemistry as a forum for non-histochemical scientific societies

“…[39][40][41] Chondrogenesis and osteogenesis were investigated not only during normal embryological development but also in the attempt to elucidate the origin of joint diseases, such as osteoarthritis. [42][43][44][45][46] Immunohistochemistry was essential to demonstrate the embryological origin of hemopoietic cells in non-mammalian vertebrates, 47,48 and to describe the interaction of non-myelinating Schwann cells with immune cells in the mouse lymphoid organs. [49][50][51] The basic cell mechanisms of apoptosis and autophagy proved to play key roles during the pre-and postnatal development of the cochlea in rodents 27,52,53 as well as during senescence in culture of sheep neurons and astrocytes.…”