Lithium chloride modulates chondrocyte primary cilia and inhibits Hedgehog signaling.
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.
*Institute of Bioengineering, School of Engineering and Materials Science, Queen Mary University of London, London, United Kingdom; and Dunedin School of Medicine, University of Otago, Dunedin, New Zealand clare.l.thompson@qmul.ac.uk.
Clare L
CL
Thompson
*Institute of Bioengineering, School of Engineering and Materials Science, Queen Mary University of London, London, United Kingdom; and Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
Anna
A
Wiles
*Institute of Bioengineering, School of Engineering and Materials Science, Queen Mary University of London, London, United Kingdom; and Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
C Anthony
CA
Poole
*Institute of Bioengineering, School of Engineering and Materials Science, Queen Mary University of London, London, United Kingdom; and Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
Martin M
MM
Knight
D020727:ADP-Ribosylation Factors / Q000378:metabolism; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D002417:Cattle; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism*; D002923:Cilia / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D018021:Lithium Chloride / Q000494:pharmacology*; D008297:Male; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000071676:Zinc Finger Protein GLI1
C498521:Gli1 protein, rat; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606239:Ptch1 protein, rat; D011956:Receptors, Cell Surface; D000071676:Zinc Finger Protein GLI1; D020727:ADP-Ribosylation Factors; D018021:Lithium Chloride
Arl13b; cilia length; osteoarthritis