Farnesoid X receptor agonist attenuates subchondral bone osteoclast fusion and osteochondral pathologies of osteoarthritis via suppressing JNK1/2/NFATc1 pathway

Abstract

Osteoarthritis (OA) is a prevalent degenerative disease of the joint, featured by articular cartilage destruction and subchondral bone marrow lesions. Articular cartilage and subchondral bone constitute an osteochondral unit that guarantees joint homeostasis. During OA initiation, activated osteoclasts in subchondral bone ultimately result in impaired capacities of the subchondral bone in response to mechanical stress, followed by the degradation of overlying articular cartilage. Thus, targeting osteoclasts could be a potential therapeutic option for treating OA. Here, we observed that farnesoid X receptor (FXR) expression and osteoclast fusion and activity in subchondral bone were concomitantly changed during early‐stage OA in the OA mouse model established by anterior cruciate ligament transection (ACLT). Then, we explored the therapeutic effects of FXR agonist GW4064 on the osteochondral pathologies in ACLT mice. We showed that GW4064 obviously ameliorated subchondral bone deterioration, associated with reduction in tartrate‐resistant acid phosphatase (TRAP) positive multinuclear osteoclast number, as well as articular cartilage degradation, which were blocked by the treatment with FXR antagonist Guggulsterone. Mechanistically, GW4064 impeded osteoclastogenesis through inhibiting subchondral bone osteoclast fusion via suppressing c‐Jun N‐terminal kinase (JNK) 1/2/nuclear factor of activated T‐cells 1 (NFATc1) pathway. Taken together, our results present evidence for the protective effects of GW4064 against OA by blunting osteoclast‐mediated aberrant subchondral bone loss and subsequent cartilage deterioration. Therefore, GW4064 demonstrates the potential as an alternative therapeutic option against OA for further drug development.

Effect of gut flora mediated‐bile acid metabolism on intestinal immune microenvironment

“…Osteoclasts originate in the mononuclear macrophage system, it is a special kind of terminally differentiated cell. FXR agonist inhibits c-Jun N-terminal kinase (JNK) 1/2/nuclear factor of activated T-cells 1 (NFATc1) pathway (JNK1/2/NFATc1) and alleviates subchondral osteoclast fusion (Figure 3c) [84]. Kupffer cells, which were liver macrophages, decreased TNF-α and increased IL-10 expression with the activation of FXR by GW4064 [85].…”

Effect of gut flora mediated-bile acid metabolism on intestinal immune microenvironment

“…Osteoclasts originate in the mononuclear macrophage system, which ich is a special type of terminally differentiated cell. FXR agonists inhibit the c-Jun N-terminal kinase (JNK) 1/2/nuclear factor of activated T-cells 1 (NFATc1) pathway JNK1/2/NFATc1 and alleviate subchondral osteoclast fusion 83 . Kupffer cells, which are liver macrophages, showed decreased TNF-α and increased IL-10 expression with the activation of FXR by GW4064 84 .…”

Mesenchymal stem cell-derived exosomes as a promising cell-free therapy for knee osteoarthritis

“…Compared to articular cartilage, subchondral bone exhibits a greater capacity in response to surrounding mechanical stress ( Hu et al, 2021 ). In early-stage OA, accelerated bone resorption and reduced subchondral bone plate thickness precede obvious cartilage degeneration ( Kazemi and Williams, 2021 ; Hu et al, 2022 ). Subsequently, cartilage destruction occurs primarily in areas where the subchondral bone plate thickness is decreased.…”