Increased joint loading induces subchondral bone loss of the temporomandibular joint via the RANTES-CCRs-Akt2 axis

Abstract

Early-stage temporomandibular joint osteoarthritis (TMJOA) is characterized by excessive subchondral bone loss. Emerging evidence suggests that TMJ disc displacement is involved, but the pathogenic mechanism remains unclear.Here, we established a rat model of TMJOA that simulated disc displacement and a capacitance-based force sensing system to directly measure articular surface pressure in vivo. Micro-CT, histological staining, immunofluorescence staining, immunohistochemistry staining, and Western blot were used to assess pathological changes and underlying mechanism of TMJOA in the rat model in vivo as well as in RAW264.7 cells in vitro. We found that disc displacement led to significantly higher pressure on articular surface, which caused subchondral bone loss rapidly via activation of RANTES-CCRs-Akt2 axis. Inhibition of RANTES or Akt2 attenuated subchondral bone loss and resulted in improved subchondral bone microstructure. Cytological studies substantiated that RANTES regulated osteoclast formation by binding to its receptor CCRs and activating Akt2 pathway. The clinical evidence further supported that RANTES was a potential biomarker for predicting subchondral bone loss in early-stage TMJOA. Taken together, this study demonstrates important functions of RANTES-CCRs-Akt2 axis in the regulation of subchondral bone remodeling and provides further knowledge of how disc displacement causes TMJOA.

Excessive load promotes temporomandibular joint chondrocyte apoptosis via Piezo1/endoplasmic reticulum stress pathway

“…The aetiology of TMJ condylar cartilage degeneration is multifaceted, involving malocclusion, trauma, excessive loading, individual development, genetic factors, and systemic diseases like rheumatoid arthritis. 37 However overloading stress stands out as a significant etiological factor in TMJ osteoarthritis, contributing to the progressive degeneration of temporomandibular condylar cartilage and hindering chondrocyte self‐repair. 31 Studies have highlighted a notable correlation between mouth breathing in adolescents and condylar morphology.…”

“…Therefore, exploring the mechanisms of chondrocyte apoptosis in joint cartilage is significant for targeted therapy of TMJ osteoarthritis. The aetiology of TMJ condylar cartilage degeneration is multifaceted, involving malocclusion, trauma, excessive loading, individual development, genetic factors, and systemic diseases like rheumatoid arthritis 37 . However overloading stress stands out as a significant etiological factor in TMJ osteoarthritis, contributing to the progressive degeneration of temporomandibular condylar cartilage and hindering chondrocyte self‐repair 31 .…”

The role of monocyte/macrophage chemokines in pathogenesis of osteoarthritis: A review

“…By contrast, improper expression of these chemokines in OA significantly increased the transformation of macrophages into osteoclasts and inhibited the production and expression of OBs, thus promoting bone resorption and leading to osteopenia and bone mineralisation, which could accelerate the progression of osteoporosis in patients with OA (Boyce et al, 2023;Dapunt et al, 2014;Feng et al, 2022;Toh et al, 2004;Vallet et al, 2011). Some studies have found that CCL2…”

“…In normal subchondral bone, these chemokines are involved in the mediation of macrophage migration and osteoclast formation, maintaining the balance between bone formation and bone resorption. By contrast, improper expression of these chemokines in OA significantly increased the transformation of macrophages into osteoclasts and inhibited the production and expression of OBs, thus promoting bone resorption and leading to osteopenia and bone mineralisation, which could accelerate the progression of osteoporosis in patients with OA (Boyce et al., 2023; Dapunt et al., 2014; Feng et al., 2022; Toh et al., 2004; Vallet et al., 2011). Some studies have found that CCL2 can promote the release of some pro‐inflammatory factors and activate inflammatory responses to aggravate bone tissue destruction, including a decrease in the number of subchondral trabeculae, thinning of the cortical bone plate, and an increase in the mineral/matrix ratio (Morrison et al., 2014; Raghu et al., 2017; Villiger et al., 1992a, 1992b).…”

C-C Motif Chemokine Ligand 5 (CCL5) Promotes Irradiation-Evoked Osteoclastogenesis

“…The expression profile of 110+ SASP components secreted by IR-induced senescent OCYs was established in our laboratory previously using a cellular multifactor antibody microarray assay [8,17]. Based on the results of previous experiments, in conjunction with the bioinformatic analysis and literature search, in this study, we focus on the C-C motif chemokine ligand 5 (CCL5), which plays a regulatory role in osteoclastogenesis [18][19][20][21], given the fact that CCL5 promotes the migration of OC precursor cells in a concentration-dependent manner, enhancing osteoclastogenesis. Accordingly, CCL5 can not only stimulate the elevated intracellular Ca 2+ concentrations and prolonged calcium flow, which results in hyperphosphorylation and extensive cellular activation, but it can also activate the JAK1/STAT3 pathway, which is a stressful inflammatory signaling pathway that has the ability to cascade the production and secretion of key SASP factors, especially CCL5, that regulate bone metabolism.…”