Antagonism between pro-chondrogenic growth factors and pro-inflammatory cytokines and the chondrogenic differentiation of human

INTRODUCTION: Cartilage loss through trauma or arthritis presents an important clinical challenge. Because sources of autograft are limited, the generation of cartilage repair tissue using mesenchymal progenitor cells (MPCs) – either ex vivo or in situ – represents an attractive alternative. Various members of the transforming growth factor (TGF) superfamily have been shown to direct chondrogenesis both in vitro and in vivo. However, in situ chondrogenesis would often need to occur in the presence of inflammatory mediators produced in response to injury or disease, such as interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ). Our previous data have confirmed that IL-1β and TNF-α powerfully inhibit the TGF-β1-induced differentiation of human bone marrow-derived MPCs through activation of one or more nuclear factor-κB (NF-κB) pathways [1]. However, recent studies have provided evidence that bone morphogenetic protein-7 (BMP-7) inhibits cartilage degeneration in various animal models of injury and arthritis. Here we examined the antagonism between pro-chondrogenic growth factors and pro-inflammatory cytokines with respect to MPC differentiation, comparing TGF-β1 and BMP-7 specifically. In addition, we present a modification to the aggregate culture model for chondrogenesis that offers a more expeditious analysis of transcription factor activity within human MPCs.