Osteoarthritis (OA) is a degenerative joint disease that involves the destruction of articular cartilage and eventually leads to disability. Molecules that promote the selective differentiation of multipotent mesenchymal stem cells (MSCs) into chondrocytes may stimulate the repair of damaged cartilage. Using an image-based high-throughput screen, we identified the small molecule kartogenin, which promotes chondrocyte differentiation (median effective concentration = 100 nM), shows chondroprotective effects in vitro, and is efficacious in two OA animal models. Kartogenin binds filamin A, disrupts its interaction with the transcription factor core-binding factor β subunit (CBFβ), and induces chondrogenesis by regulating the CBFβ-RUNX1 transcriptional program. This work provides new insights into the control of chondrogenesis that may ultimately lead to a stem cell-based therapy for osteoarthritis.

SignificanceThe ReFRAME collection of 12,000 compounds is a best-in-class drug repurposing library containing nearly all small molecules that have reached clinical development or undergone significant preclinical profiling. The purpose of such a screening collection is to enable rapid testing of compounds with demonstrated safety profiles in new indications, such as neglected or rare diseases, where there is less commercial motivation for expensive research and development. Providing the academic and nonprofit research community access to a high-value compound collection and related screening data in an open-access platform should provide new tool compounds for biomedical research, as well as accelerate drug-discovery and/or development programs aimed at developing new therapies for diverse unmet medical needs.

Fluorescent and luminescent reporters that signal molecular events of interest by modulating the ratio of peaks in their emission profile have advantages over reporters that simply modulate their emission intensity, since ratiometric measurement is concentration-independent and allows them to be effective in complex contexts, such as living cells or sensor microarrays. We herein describe a general platform for the design of ratiometric probes based on a heterometallic Tb(3+)/Eu(3+) bis-lanthanide ensemble, consisting of a mixture, or "cocktail", of otherwise identical heterometalated chelates. The chelate contains an organic photon antenna that sensitizes the Tb(3+)/Eu(3+) luminescence. The contributions of the two metals to the composite luminescence spectrum can be tuned to the same relative scale by adjusting the stoichiometry of the cocktail, allowing subtle changes in their ratio to be accurately measured. Importantly, the ratio responds to chemical and environmental changes experienced by the photon antenna, making the system an ideal platform for the design of chemical and enzymatic probes. As proofs of concept, we describe a ratiometric probe for esterase activity and a polarity-responsive ratiometric sensor.

SignificanceThe beneficial effects of LXR-pathway activation have long been appreciated, but clinical application of synthetic LXR ligands has been limited by coactivation of SREBP1c and consequent hypertriglyceridemia. Natural LXR ligands such as desmosterol do not promote hypertriglyceridemia because of coordinate down-regulation of the SREBP pathway. Here we demonstrate that synthetic desmosterol mimetics activate LXR in macrophages both in vitro and in vivo while suppressing SREBP target genes. Unexpectedly, desmosterol and synthetic desmosterol mimetics have almost no effect on LXR activity in hepatocytes in comparison with conventional synthetic LXR ligands. These findings reveal cell-specific differences in LXR responses to natural and synthetic ligands in macrophages and liver cells that provide a conceptually new basis for future drug development.