Primary cilia mediate mechanosensing in bone cells by a calcium-independent mechanism

Abstract

Primary cilia are sensory organelles that translate extracellular chemical and mechanical cues into cellular responses. Bone is an exquisitely mechanosensitive organ, and its homeostasis depends on the ability of bone cells to sense and respond to mechanical stimuli. One such stimulus is dynamic fluid flow, which triggers biochemical and transcriptional changes in bone cells by an unknown mechanism. Here we report that bone cells possess primary cilia that project from the cell surface and deflect during fluid flow and that these primary cilia are required for osteogenic and bone resorptive responses to dynamic fluid flow. We also show that, unlike in kidney cells, primary cilia in bone translate fluid flow into cellular responses in bone cells independently of Ca 2+ flux and stretch-activated ion channels. These results suggest that primary cilia might regulate homeostasis in diverse tissues by allowing mechanical signals to alter cellular activity via tissue-specific pathways. Our identification of a mechanism for mechanotransduction in bone could lead to therapeutic approaches for combating bone loss due to osteoporosis and disuse.

Effect of in vitro stress‐deprivation and cyclic loading on the length of tendon cell cilia in situ

“…7,9,29 Primary cilia are known to participate in a number of biological processes ranging from chemo-and mechanosensitivity to the transduction of paracrine signaling cascades that are critical for the development and maintenance of different tissues and organs. 30 These sensory organelles have been described in a variety of connective tissue cells [6][7][8][9][10][11] and have been implicated in the homeostasis of the skeleton. 16,8 It has been postulated that primary cilia projecting from cells into the extracellular matrix are exposed to fluid flow shear stress, mechanical deformation, and/or pressure gradients which, in turn, trigger a cellular response.…”

“…30 These sensory organelles have been described in a variety of connective tissue cells [6][7][8][9][10][11] and have been implicated in the homeostasis of the skeleton. 16,8 It has been postulated that primary cilia projecting from cells into the extracellular matrix are exposed to fluid flow shear stress, mechanical deformation, and/or pressure gradients which, in turn, trigger a cellular response. 16 It has also been suggested that the magnitude and duration of these physical signals could lead to the remodeling of cilia structure through a change in its length via a feedback mechanism.…”

“…1 Primary cilia are sensory organelles for the detection and transmission of mechanical and chemical information from the extracellular environment of cells [2][3][4] and are known to function as mechanosensors in several connective tissue cell types, including tenocytes, osteocytes, and chondrocytes. [5][6][7][8][9][10][11] The expression of transmembrane extracellular matrix receptors (integrins) on the cilium strongly suggests that the cilium has the molecular machinery necessary to act as a mechanosensory linkage between the ECM and cytoplasmic organelles. 10 Bending or stretching of the cilium can tug on such integrins, thus generating a cascade of events ranging from internal calcium release 12 to the activation of genes 10 and signaling molecules.…”

Osteocytes, mechanosensing and Wnt signaling

“…It remains to be determined if PKD1 and PKD2 function in a similar manner in both kidney and bone (86). Recently, Jacobs and colleagues have shown that primary cilia in bone cells do not mediate calcium flux in response to fluid flow, therefore the mechanism used by cilia in bone cells is distinct from that of kidney cells (76). Reducing the number of cilia reduces the induction of osteopontin in MC3T3 osteoblast cells, the induction of prostaglandin in both MC3T3 and MLOY4 osteocyte cells, and the increase of COX2 and OPG/RANKL ratio in MLOY4 cells in response to fluid flow shear stress.…”

From streaming‐potentials to shear stress: 25 years of bone cell mechanotransduction

“…59 Malone et al 60 have recently demonstrated that fluid flow deflects the primary cilium in models of osteoblastic and osteocytic cells, and disruption of the cilium via pharmacological or genetic means diminishes the effects of fluid flow on prostaglandin production and osteopontin expression. However, disrupting the primary cilium did not affect the ability of osteoblastic cells to respond to fluid flow with an increase in intracellular calcium, as is the case in kidney cells, 61 suggesting that other mechanosensory mechanisms must work in conjunction with the cilium.…”