Lengthening primary cilia enhances cellular mechanosensitivity

Abstract

The primary cilium is a mechanosensor in a variety of mammalian cell types, initiating and directing intracellular signaling cascades in response to external stimuli. When primary cilia formation is disrupted, cells have diminished mechanosensitivity and an abrogated response to mechanical stimulation. Due to this important role, we hypothesized that increasing primary cilia length would enhance the downstream response, and therefore, mechanosensitivity. To test this hypothesis, we increased osteocyte primary cilia length with fenoldopam and lithium and found that cells with longer primary cilia are more mechanosensitive. Furthermore, fenoldopam treatment potentiated adenylyl cyclase activity and was able to recover primary cilia form and sensitivity in cells with impaired cilia. This work demonstrates that modulating the structure of the primary cilium directly impacts cellular mechanosensitivity. Our results implicate cilium length as a potential therapeutic target for combating numerous conditions characterized by impaired cilia function.

Topography of calcium phosphate ceramics regulates primary cilia length and TGF receptor recruitment associated with osteogenesis

“…Furthermore, in mesenchymal stem cells, primary cilia are necessary for mechanosignalling [47] which also regulated differentiation. Other recent studies report that cilia elongation increases mechanosignalling in bone [48]. Therefore changes in cilia length in response to osteogenic TCP topography may modulate in vivo bone formation through altered mechanosignalling in addition to regulation of osteogenesis.…”

The primary cilium as a signaling nexus for growth plate function and subsequent skeletal development

“…FGF was believed to act independently of the cilium until a study revealed that cilia shorten in zebrafish embryos containing a knockdown of FGF receptor 1 (FGFR1) . Recent work in our lab and others suggests that lengthening cilia enhances their mechanosensitivity, so it is perhaps not surprising that FGF mutants with shorter cilia demonstrate developmental abnormalities . In the growth plate, FGF signaling inhibits chondrocyte proliferation and accelerates the onset and rate of hypertrophic differentiation .…”

Primary cilia: Cell and molecular mechanosensors directing whole tissue function

“…We recently showed that treating osteocytes with fenoldopam or lithium, two small molecules with distinct mechanisms of action, increases primary cilia length [77]. Moreover, osteocytes with longer cilia are more mechanosensitive, displaying increased osteogenesis in response to fluid flow.…”

“…Longer cilia may allow for a greater number of cilia-specific proteins and signaling molecules within the microdomain to potentiate mechanosensing [52,54]. Cells treated with the cilium lengthening agent, fenoldopam, also display significant increases in production of AC6, key to primary cilia-mediated mechanotransduction [77,78]. …”