Osteoarthritis (OA) is an
age-related degenerative disease. Oxidative stress (OS) modulates
OA pathogenesis by enhancing chondrocyte apoptosis and extracellular
matrix (ECM) degeneration via activation of the endoplasmic reticulum
(ER) stress. Prior studies revealed that safranal plays a critical
role in multiple diseases treatments, but there are no reports on
its effect on OA. Therefore, investigating the effect of safranal
on OA is needed. As a compound that can lead excessive reactive oxygen
species (ROS) accumulation, tert-butyl hydroperoxide
(TBHP) was used to induce OS and OS-mediated endoplasmic reticulum
(ER) stress for imitating OA in vitro. Besides, the bilateral medial
meniscus was removed to induce joint instability and excessive friction
of the joint surface to establish destabilization of medial meniscus
for imitating the initiation and progression of OA in vivo. We, next,
conducted Western blot and RT-PCR analyses to identify biomarkers
of the underlying signaling pathway. Our results demonstrated that
30 μM safranal strongly upregulated Sirt1 expression, suppressed
TBHP-mediated ER stress, and, in turn, prevented chondrocyte apoptosis
and ECM degeneration. Furthermore, compared with the other two classic
signaling pathways of ER stress, safranal can inhibit the PERK-eIF2α-CHOP
axis at the lower concentration (5 and 15 μM). In vivo, using
Safranin O staining, X-ray, immunofluorescence (IF), and immunohistochemical
(IHC) staining, we demonstrated that OA progression can be postponed
with intraperitoneal injection of 90 and 180 mg/kg safranal in an
OA mouse model. Taken together, our analyses revealed that safranal
can potentially prevent OA development.