Primary Cilia: A Cellular Regulator of Articular Cartilage Degeneration

Table 1

The protein or signaling factors in the chondrocyte primary cilia.

Name	Definition	Location	Study related to cartilage development	Ref.
TRPV4	A nonselective cation channel	Ciliary membrane and axoneme	In this study, TRPV4 activation by mechanical, hypoosmotic, and pharmaceutical stimulation blocked IL-1β-mediated inflammatory signaling and destruction of the articular cartilage matrix by HDAC6-dependent modulation of ciliary tubulin.	[28]
PC1	Eleven transmembrane helix proteins	Cell membrane and cytoplasm	Wann et al. have demonstrated that the chondrocyte cilium is the downstream receptor of ATP-induced Ca^2+ signaling and suggest that defective PC1 processing leads to disrupted signaling in Tg737^ORPK mutant cells.	[29]
PC2	Six transmembrane helices	Ciliary membrane	Thompson et al. have reported that upon mechanical stimulation, PC2 ciliary localization increases, which activates purinergic Ca^2+ signaling, upregulates matrix gene expression, and protects cilia from mechanically induced disassembly.	[30]
HDAC6	a tubulin deacetylase	Axoneme	Fu et al. have shown that mechanical loading activates HDAC6 and disrupts tubulin acetylation and cilia elongation, which inhibits IL-1β-induced release of proinflammatory mediators, nitric oxide (NO), and prostaglandin E2 (PGE 2).	[31]
Arl13b	The membrane bound GTPase, a key regulator of the ciliary trafficking	Ciliary membrane and axoneme	Thorpe et al. have demonstrated that the prevalence and length of normalized primary cilia are dramatically reduced and Arl13b expression at the distal tip is increasing in AKU chondrocytes, which manifests itself as articular cartilage degeneration, resulting in inhibition of ligand-induced hedgehog signaling.	[32]
HIF-2α	a DNA-binding transcription factor	Ciliary base	This study indicates that the primary cilium regulates HIF signaling during inflammation.	[33]
TGF-βR	The orphan G-protein-coupled receptor	Ciliary pocket	Kawasaki et al. have reported that TGF-β suppresses Ift88 expression and reduces the length of primary cilia in chondrocytic ATDC5 cells, which may be the mechanisms of cartilage pathophysiology.	[34]
Gpr161	The orphan G-protein-coupled receptor	Primary cilia	Hwang et al. have reported that Gpr161 regulates limb patterning, endochondral, and intramembranous skeletal morphogenesis in a cilium-dependent way.	[35]

PC1: polyc ystin-1; PC2: polycystin-2; HDAC6: histone deacetylase 6; Arl13b: ADP-ribosylation factor-like protein 13B; HIF-2α: hypoxia-inducible factor 2 alpha.