Abstract
Pain is the most prominent symptom of osteoarthritis (OA) progression. However, the relationship between pain and OA progression remains largely unknown. Here we report osteoblast secret prostaglandin E2 (PGE2) during aberrant subchondral bone remodeling induces pain and OA progression in mice. Specific deletion of the major PGE2 producing enzyme cyclooxygenase 2 (COX2) in osteoblasts or PGE2 receptor EP4 in peripheral nerve markedly ameliorates OA symptoms. Mechanistically, PGE2 sensitizes dorsal root ganglia (DRG) neurons by modifying the voltage-gated sodium channel NaV1.8, evidenced by that genetically or pharmacologically inhibiting NaV1.8 in DRG neurons can substantially attenuate OA. Moreover, drugs targeting aberrant subchondral bone remodeling also attenuates OA through rebalancing PGE2 production and NaV1.8 modification. Thus, aberrant subchondral remodeling induced NaV1.8 neuronal modification is an important player in OA and is a potential therapeutic target in multiple skeletal degenerative diseases.
Highlights
Subchondral bone is an integral component of the joint, absorbing compressive forces during movement (Martel-Pelletier et al, 2016)
We found that when bone mass is decreased, the enzymatic activity of cyclooxygenase 2 (Cox2) in osteoblastic lineage cells was significantly increased and catalyzes more arachidonic acid into prostaglandin E2 (PGE2)
We found that the NaV1.8+ neurons labeled by DiI significantly increased in the dorsal root ganglia (DRG) neurons of OA rats relative to sham-operated rats (Figure 1g,h), indicating that DiI was transported into DRG neurons by the sensory fibers innervated subchondral bone in a retrograde manner
Summary
Subchondral bone is an integral component of the joint, absorbing compressive forces during movement (Martel-Pelletier et al, 2016). Physiological subchondral bone remodeling maintains its structural integrity and supports the overlying articular cartilage. Age or trauma (Hayami et al, 2004) related alteration of subchondral bone is a principal risk factor of osteoarthritis (OA), the most common joint disease (Berenbaum et al, 2018) characterized by cartilage destruction (Glasson et al, 2005; Kim et al, 2014a), subchondral sclerosis (Suri et al, 2007) and synovitis (Benito et al, 2005; Sellam and Berenbaum, 2010). The major local source is not clearly defined (Malfait and Schnitzer, 2013), there is evidence showing that synovitis (Sellam and Berenbaum, 2010) and subchondral bone marrow lesion (BML) are highly relevant to OA pain. We previously showed that aberrant subchondral bone remodeling in response to altered
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