Emerging role of primary cilia as mechanosensors in osteocytes

Abstract

The primary cilium is a solitary, immotile microtubule-based extension present on nearly every mammalian cell. This organelle has established mechanosensory roles in several contexts including kidney, liver, and the embryonic node. Mechanical load deflects the cilium, triggering biochemical responses. Defects in cilium function have been associated with numerous human diseases. Recent research has implicated the primary cilium as a mechanosensor in bone. In this review, we discuss the cilium, the growing evidence for its mechanosensory role in bone, and areas of future study.

Figure 1

Schematic showing structure of primary cilium. The structure is segmented into the axoneme and basal body. Kinesin-2 motors (blue) regulate anterograde IFT while Dynein motors (red) regulate retrograde IFT along the microtubules (green) in the axoneme.

Figure 2

Proposed Pkd1 cilia-mediated pathway. Polycystin-1 (green) and polycystin-2 (blue) form the Polcystin complex. This complex is thought to respond to flow by allowing an extracellular calcium influx.

Figure 3

Proposed adenylyl cyclase cilia-mediated pathway. The flow-induced calcium influx inhibits adenylyl cyclase 6 (blue, AC6), which in turn leads to a decrease in cyclic AMP (green, cAMP) and a decrease in activated protein kinase A (purple, PKA).

Figure 4

Proposed Inversin cilia-mediated pathway. Fluid flow upregulates Inversin (blue, Inv). Inversin forms a complex with cytoplasmic Dishevelled (green, Dsh), increasing its ubiquitination and essentially inhibiting the canonical Wnt pathway.

Figure 5

Proposed microenvironment for the osteocyte and its primary cilium. With loading, interstitial fluid flow (blue) may bend the the primary cilium (brown) projecting from the osteocyte’s (orange) surface.