Osteoarthritis: molecular pathogenesis and potential therapeutic options
Summary
Osteoarthritis (OA) is a debilitating joint disorder that causes chronic pain, inflammation, and detrimental bone alterations. Despite significant advances in understanding OA pathogenesis, current therapeutic strategies remain inadequate in halting disease progression or providing effective pain relief, highlighting unmet clinical needs. Recent insights into OA nociceptive pathways, inflammatory mediators, and organelle dysfunction have revealed promising therapeutic targets. Specifically
Content
# Osteoarthritis: molecular pathogenesis and potential therapeutic options
*Published: 2026 Mar 4*
Osteoarthritis (OA) is a debilitating joint disorder that causes chronic pain,
inflammation, and detrimental bone alterations. Despite significant advances in
understanding OA pathogenesis, current therapeutic strategies remain inadequate
in halting disease progression or providing effective pain relief, highlighting
unmet clinical needs. Recent insights into OA nociceptive pathways, inflammatory
mediators, and organelle dysfunction have revealed promising therapeutic
targets. Specifically, OA progression is driven by mitochondrial dysfunction
(marked by accumulated damaged mitochondria with excessive ROS production and
impaired ATP synthesis), lysosomal destabilization (due to persistent
hydroxyapatite digestion causing acidification loss, membrane permeabilization,
and chondrocyte apoptosis), and unresolved ER stress (resulting from
compensatory protein overproduction that exacerbates cartilage degradation). In
this review, we aim to provide a comprehensive exploration of the nociceptive
pathways linking the knee joint to the central nervous system, shedding light on
the mechanisms underlying OA-associated pain. We further analyzed pathological
changes in bone architecture and chondrocytes, emphasizing the synergistic roles
of inflammatory cytokines and organelle-specific dysfunctions. Building on these
mechanistic insights, we delineate emerging pharmacological strategies designed
to concurrently address inflammatory cascades, restore organelle homeostasis
(via mitophagy potentiation, lysosomal integrity preservation, and ER stress
alleviation), and attenuate nociceptive signaling-thereby establishing a
multimodal therapeutic paradigm to ameliorate both structural degeneration and
clinical manifestations of OA. We also highlight advanced organelle-targeted
drug delivery systems designed to increase the therapeutic efficacy and
stability of these treatments. Collectively, these advancements provide a
framework for novel OA interventions.
DOI: 10.1038/s41392-025-02556-6