Bone Abstracts

Purpose: High osteoclastogenesis accompanies early stages of osteoarthritis (OA). Cartilage loss is reduced when osteoclasts are inhibited in mice models with bone hyperresorption. Although several evidences show that osteoclast-produced molecules affects chondrocyte metabolism, the mechanism by which inhibition of osteoclasts protects from cartilage damage is unclear. Our purpose was to investigate the role of Sphingosine 1 Phosphate, a lipid mediator secreted by osteoclasts known as mediator of bone remodeling, in chondrocyte metabolism and OA.

Methods: Primary murine chondrocytes and cartilage explants were cultured in the presence of osteoclast conditioned media (Oc-CM) to quantify matrix protein expression and proteoglycan content (RT-qPCR, WB, safranin O staining). S1P receptors antagonists, JTE-013 for S1P receptor 2 (S1PR2) and VPC 23019 for S1PR1-3 as well as siRNA strategies are used to block S1P signaling. The role of S1P signaling in OA was investigated in the DMM model by JTE-013.

Results: Femoral head explants and primary murine chondrocytes cultured in presence of Oc-CM induced lower extracellular matrix production (proteoglycan release) and higher metalloprotease expression (MMP3, MMP13, ADAMTS-4, ADAMTS-5) compared to controls. The expression of S1P receptors 1-3 was increased in chondrocytes cultured with Oc-CM, as well as the activation of their signaling pathway (MAPK). However, only the inhibition of the receptor S1PR2 by JTE-013 and RNA silencing abolished Oc-CM effect on MMP-3 and -13 in primary chondrocytes, but not those of S1PR1-R3. S1PR2 inhibition was confirmed in femoral head explants as JTE-013 reduced loss of proteoglycan and extracellular matrix degradation initially induced by Oc-CM. In OA mice, systemic administration of JTE-013 reduced OA score (5.5±0.86 vs 4±0.70)

Conclusion: Osteoclast-secreted factors disrupt the balance of chondrocyte metabolism. The activation of S1P signaling in chondrocytes by osteoclasts promotes chondrocyte catabolism, the inhibition of which prevented OA. Therefore, subchondral bone manipulations may affect chondrocyte function and OA.