Abstract
Lithium chloride (LiCl) exhibits significant therapeutic potential as a treatment for osteoarthritis. Hedgehog signaling is activated in osteoarthritis, where it promotes chondrocyte hypertrophy and cartilage matrix catabolism. Hedgehog signaling requires the primary cilium such that maintenance of this compartment is essential for pathway activity. Here we report that LiCl (50 mM) inhibits Hedgehog signaling in bovine articular chondrocytes such that the induction of GLI1 and PTCH1 expression is reduced by 71 and 55%, respectively. Pathway inhibition is associated with a 97% increase in primary cilia length from 2.09 ± 0.7 μm in untreated cells to 4.06 ± 0.9 μm in LiCl-treated cells. We show that cilia elongation disrupts trafficking within the axoneme with a 38% reduction in Arl13b ciliary localization at the distal region of the cilium, consistent with the role of Arl13b in modulating Hedgehog signaling. In addition, we demonstrate similar increases in cilia length in human chondrocytes in vitro and after administration of dietary lithium to Wistar rats in vivo. Our data provide new insights into the effects of LiCl on chondrocyte primary cilia and Hedgehog signaling and shows for the first time that pharmaceutical targeting of the primary cilium may have therapeutic benefits in the treatment of osteoarthritis.
Highlights
Lithium chloride (LiCl) exhibits significant therapeutic potential as a treatment for osteoarthritis
We report that LiCl induces cilia elongation in human articular chondrocytes in vitro and in vivo using a rat model designed to mimic long-term lithium treatment in human patients
After 24 h r-Indian hedgehog (Ihh) treatment, real-time PCR analysis showed that the mRNA levels of GLI1 (Fig. 1A) and PTCH1 (Fig. 1B) were significantly increased by 4.48and 3.16-fold, respectively
Summary
Lithium chloride (LiCl) exhibits significant therapeutic potential as a treatment for osteoarthritis. A drug previously used for the treatment of bipolar disorder [1,2,3], has recently been shown to exhibit significant therapeutic potential as a treatment for arthritis [4, 5] These studies show that LiCl inhibits cartilage degradation in vitro in response to the inflammatory cytokine IL-1. LiCl disrupts the downstream activation of p38 MAPK and nuclear factor k-light-chain-enhancer of activated B cells (NF-kB) in response to IL-1, inhibiting the induction of catabolic enzymes such as A disintegrin and metalloproteinase with thrombospondin motifs 5 and matrix metalloproteinases 3 and 13. The anterograde motor kinesin 2 is responsible for the transport of IFT cargo, like tubulin, from the base of the cilium to the distal tip, while cytoplasmic dynein 2 mediates retrograde
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