Periodic Mechanical Stress Stimulates Cav-1-Dependent IGF-1R Mitogenic Signals in Rat Chondrocytes Through ERK1/2

Abstract

Background/Aims: The biological effects of periodic mechanical stress on the mitogenesis of chondrocytes have been studied extensively over the past few years. However, the mechanisms underlying the ability of chondrocytes to sense and respond to mechanical stimuli remain to be determined. In the current study, we analyzed the mechanisms by which periodic mechanical stress is translated into biochemical signals and verified the key role of non-integrin mechanosensors including Caveolin-1 (Cav-1), and insulin-like growth factor-1 receptor (IGF-1R) in chondrocyte proliferation. Methods: Two steps were undertaken in the experiment. In the first step, the cells were maintained under static conditions or periodic mechanical stress for 0 h and 1 h prior to Western blot analysis. In the second step, the cells were pretreated with short hairpin RNA (shRNA) targeted to Cav-1 or IGF-1R or control scrambled shRNA. Moreover, they were pretreated with their selective inhibitors methyl β-cyclodextrin (MCD) or Linsitinib (OSI-906). They were maintained under static conditions or periodic mechanical stress for 1 h prior to Western blot analysis, and for 3 days, 8 h per day, prior to direct cell counting and CCK-8 assay, respectively. Results: Periodic mechanical stress significantly induced sustained phosphorylation of Cav-1 at Tyr 14 and IGF-1R at Tyr 1135/1136 . Proliferation was inhibited by pretreatment with Cav-1 inhibitor MCD and by shRNA targeted to Cav-1 in chondrocytes in response to periodic mechanical stress. Meantime, MCD and shRNA targeted to Cav-1 also attenuated IGF-1R, and extracellular signal-regulated kinase (ERK)1/2 activation. In addition, inhibiting IGF-1R activity by Linsitinib and shRNA targeted to

Mechanotransduction in meniscus fibrochondrocytes: What about caveolae?

“…Reduced levels of IGF-1 have been shown to correlate with increased catabolism of tissues, associated with increased damage of cartilage and loss of proteoglycans and chondrocytes (Wei et al, 2017). Therefore, if caveolae can regulate ERK1/2 and IGF-1R signaling in response to mechanical cues like compression, as shown by Ren et al (2018), this suggests that caveolae may play an important role in matrix homeostasis and potentially KOA pathogenesis.…”

“…The current knowledge on caveolae‐mediated mechanotransduction in KACs is scare, however, there are a few groups that have identified some interactions. The study done by Ren and colleagues in 2018 is probably the most insightful as they looked at the direct effects of caveolar inhibition on KACs exposed to compression. In this study, rat KACs were exposed or not to 1 h of periodic hydraulic pressure (i.e., compression) in either the absence or presence of caveolar disruptors, methyl‐‐cyclodextrin (M β CD) and caveolin‐1 short hairpin RNA (shRNA).…”

Periodic Mechanical Stress Inhibits the Development of Osteoarthritis via Regulating ATF3-Akt Axis

“…Several studies have reported the promoting effect of PMS on the proliferation of chondrocytes and matrix synthesis. [21][22][23][24] For example, van Valburg et al reported that joint traction provided mechanical stress to promote the repair of cartilage. 25 Additionally, Gao et al discovered that PMS significantly induced the expression of extracellular matrix (ECM) Col-2A1 and aggrecan in nucleus pulposus (NP) cells.…”