Osteoarthritis: molecular pathogenesis and potential therapeutic options

TL;DR

This paper reviews the molecular causes of osteoarthritis and explores new treatment strategies targeting cellular dysfunction and pain pathways.

Contribution

The paper introduces a multimodal therapeutic approach targeting organelle dysfunction and inflammation in osteoarthritis.

Findings

Mitochondrial dysfunction, lysosomal destabilization, and ER stress drive osteoarthritis progression.

Emerging strategies aim to restore organelle homeostasis and reduce nociceptive signaling.

Organelle-targeted drug delivery systems could improve treatment efficacy and stability.

Abstract

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.

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