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Updated: Nov 1, 2025
Software-Assisted Quantitative Measurement of Osteoarthritic Subchondral Bone Thickness
Published on: March 18, 2022
Inhibition of sphingosine 1-phosphate protects mice against chondrocyte catabolism and osteoarthritis
C Cherifi1, A Latourte2, S Vettorazzi3
1Université de Paris, BIOSCAR Inserm U1132, Paris, F-75010, France.
Objective:
Cartilage loss observed in osteoarthritis (OA) is prevented when osteoclasts in the subchondral bone are inhibited in mice. Here, we investigated the role of the osteoclast secretome and of the lipid mediator sphingosine 1-phosphate (S1P) in chondrocyte metabolism and OA.
Materials And Methods:
We used SphK1LysMCre and wild type mice to assess the effect of murine osteoclast secretome in chondrocyte metabolism. Gene and protein expressions of matrix metalloproteinase (Mmp) were quantified in chondrocytes and explants by RT-qPCR and Western blots. SphK1LysMCre mice or wild type mice treated with S1P2 receptor inhibitor JTE013 or anti-S1P neutralizing antibody sphingomab are analyzed by OA score and immunohistochemistry.
Results:
The osteoclast secretome increased the expression of Mmp3 and Mmp13 in murine chondrocytes and cartilage explants and activated the JNK signaling pathway, which led to matrix degradation. JTE013 reversed the osteoclast-mediated chondrocyte catabolism and protected mice against OA, suggesting that osteoclastic S1P contributes to cartilage damage in OA via S1P/S1P2 signaling. The activity of sphingosine kinase 1 (SphK1) increased with osteoclast differentiation, and its expression was enhanced in subchondral bone of mice with OA. The expression of Mmp3 and Mmp13 in chondrocytes was low upon stimulation with the secretome of Sphk1-lacking osteoclasts. Cartilage damage was significantly reduced in SphK1LysMCre mice, but not the synovial inflammation. Finally, intra-articular administration of sphingomab inhibited the cartilage damage and synovial inflammation.
Conclusions:
Lack of S1P in myeloid cells and local S1P neutralization alleviates from osteoarthritis in mice. These data identify S1P as a therapeutic target in OA.
Insights
Sphingosine 1-phosphate (S1P) from osteoclasts drives osteoarthritis (OA) cartilage damage. Inhibiting S1P or its signaling pathways in myeloid cells significantly reduced OA progression in mice, identifying S1P as a therapeutic target.
Area of Science:
- Biochemistry
- Immunology
- Orthopedics
Background:
- Osteoarthritis (OA) is characterized by cartilage degradation, often linked to subchondral bone osteoclast activity.
- The role of osteoclast-derived factors, particularly lipid mediators like sphingosine 1-phosphate (S1P), in OA pathogenesis remains incompletely understood.
Purpose of the Study:
- To investigate the impact of the osteoclast secretome and S1P on chondrocyte metabolism and OA development in mice.
- To explore the therapeutic potential of targeting S1P signaling in OA.
Main Methods:
- Utilized SphK1LysMCre and wild-type mice to assess osteoclast secretome effects on chondrocytes.
- Quantified matrix metalloproteinase (Mmp) expression via RT-qPCR and Western blots.
- Administered S1P receptor inhibitor (JTE013) and anti-S1P antibody (sphingomab) to evaluate OA progression, employing OA scoring and immunohistochemistry.
Main Results:
- Osteoclast secretome upregulated Mmp3 and Mmp13 in chondrocytes, activating JNK signaling and promoting matrix degradation.
- S1P signaling via the S1P2 receptor was identified as a key mediator of osteoclast-induced chondrocyte catabolism.
- Sphingosine kinase 1 (SphK1) activity and expression were elevated in OA, and its absence in myeloid cells reduced cartilage damage.
- Sphingomab treatment effectively inhibited both cartilage damage and synovial inflammation.
Conclusions:
- Osteoclast-derived S1P contributes significantly to cartilage damage in OA through S1P/S1P2 signaling.
- Targeting S1P in myeloid cells or neutralizing S1P locally demonstrates a therapeutic benefit in mouse models of OA.
- These findings highlight S1P as a promising therapeutic target for osteoarthritis.
