Role of Interleukin‐10 in Endochondral Bone Formation in Mice: Anabolic Effect via the Bone Morphogenetic Protein/Smad Pathway

Abstract

Objective. Interleukin-10 (IL-10) is a pleiotropic immunoregulatory cytokine with a chondroprotective effect that is elevated in cartilage and synovium in patients with osteoarthritis. However, the role of IL-10 during endochondral bone formation and its mechanism of action have not been elucidated.Methods. IL-10 -/-mice and IL-10-treated tibial organ cultures were used to study loss and gain of IL-10 functions, respectively, during endochondral bone formation. Primary chondrocytes from the long bones of mouse embryos were cultured with and without IL-10. To assess the role of IL-10 in chondrogenic differentiation, we conducted mesenchymal cell micromass cultures.Results The main pathologic feature of osteoarthritis (OA) is gradual loss of cartilage from exposure to repetitive loading. The initial response of chondrocytes to external mechanical loading is adaptation; that is, they become metabolically active and proliferative (1). However, repetitive stress induces hypertrophic differentiation and, eventually, chondrocyte apoptosis. During this process, the balance between anabolic and catabolic signaling pathways in which SOX9 and RUNX-2, respectively, function as major regulatory transcription factors is critical in determining the fate of chondrocytes (2,3). Several cytokines can affect the expression of SOX9 and RUNX-2 via complex autocrine and paracrine loops and, as a consequence, have an effect on the progression of OA (4,5).The physiologic and pathologic roles of the main catabolic cytokines, such as interleukin-1␤ (IL-1␤) and tumor necrosis factor ␣ (TNF␣), have been well established in chondrocyte biology (4).

Concentration‐dependent, dual roles of IL‐10 in the osteogenesis of human BMSCsviaP38/MAPK and NF‐κB signaling pathways

“…IL-10 suppresses the osteogenesis of mouse bone-marrow cells via inhibition of TGF-b1 synthesis or production (13,56). IL-10 acts as a stimulator of chondrogenic or hypertrophic differentiation in endochondral bone formation in mice via activation of the BMP-Smad signaling pathway (49). However, we found that IL-10 did not affect the AKT, STAT3, or Smad signaling pathways in hBMSCs during osteogenic differentiation (see Supplemental Fig.…”

“…Dresner-Pollak et al (12) revealed that IL-10 knockout mice had reduced bone mass, increased mechanical fragility, and suppressed bone formation (11). Jung et al (49) found that the tibial growth plates of IL-10 knockout mice exhibited shortening of the proliferating zone. However, Van Vlasselaer et al (13,14) reported that IL-10 (2.5 3 10 3 U/ml) suppressed the osteogenic differentiation of mouse bone-marrow cells.…”

Expression of synovial fluid biomarkers in patients with knee osteoarthritis and meniscus injury

“…In OA, the level of IL-10 in cartilage and the synovium are elevated (23). Studies on synovial fluid levels of IL-10 in patients with MI are limited, and our study shows that patients with MI have higher levels of IL-10 in their synovial fluids in relation to patients with OA.…”

Extracellular signaling molecules to promote fracture healing and bone regeneration

“…This is the probable mechanism for enhanced proliferating zone of growth plates in IL-10 expressing mice versus IL-10 knockout mice A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT (16). Since fracture repair recapitulates development in many aspects, IL-10 may also contribute to more robust callus formation in fracture repair.…”