The primary cilium as a novel extracellular sensor in bone

Abstract

Mechanically induced adaptation of bone is required to maintain a healthy skeleton and defects in this process can lead to dramatic changes in bone mass, resulting in bone diseases such as osteoporosis. Therefore, understanding how this process occurs could yield novel therapeutics to treat diseases of excessive bone loss or formation. Over the past decade the primary cilium has emerged as a novel extracellular sensor in bone, being required to transduce changes in the extracellular mechanical environment into biochemical responses regulating bone adaptation. In this review, we introduce the primary cilium as a novel extracellular sensor in bone; discuss the in vitro and in vivo findings of primary cilia based sensing in bone; explore the role of the primary cilium in regulating stem cell osteogenic fate commitment and finish with future directions of research and possible development of cilia targeting therapeutics to treat bone diseases.

Keywords: bone; fluid flow; mechanotransduction; osteocyte; primary cilium; stem cell.

Figure 1

Immunofluorescence image of a (A) MC3T3 (pre-osteoblast) and (B) human mesenchymal stem cell demonstrating the presence of a primary cilium as a rod like structure in the peri-nuclear region of the cell.

Figure 2

(A) Immunofluorescence image of adenylyl cyclase 6 localization to the osteocyte primary cilium (adapted from Kwon et al., 2011). (B) Illustration of the molecular mechanism of cilia-mediated mechanosensing in bone.

Figure 3

Schematic of the Cre-lox system used to generate of bone specific primary cilium knockout mouse.

Figure 4

(A) Representative images of loaded ulnae of Colα1(I) 2.3-Cre;Kif3a^fl/fl (top) and control (bottom) mice. (B,C) Relative mineral apposition rate (rMAR, μm per day), and bone formation rate (rBFR/BS, μm³/μm² per year), of mechanically loaded mice. Adapted from Temiyasathit et al. (2012).

Figure 5

Illustration of proposed signaling downstream of cilia-mediated mechanosensing in bone. PKA is known to activate the ERK1/2-CREB signaling cascade and also inhibit GSK-3β-mediated degradation of the transcription factor β-Catenin. Both pathways have been shown to be involved in fluid flow mechanotransduction in bone.