Journal Article

Periosteal progenitors contribute to load-induced bone formation in adult mice and require primary cilia to sense mechanical stimulation

Moore, Emily R., Zhu, Ya Xing, Ryu, Han Seul, Jacobs, Christopher R.

2018

Overview

Background The fully developed adult skeleton adapts to mechanical forces by generating more bone, usually at the periosteal surface. Progenitor cells in the periosteum are believed to differentiate into bone-forming osteoblasts that contribute to load-induced adult bone formation, but in vivo evidence does not yet exist. Furthermore, the mechanism by which periosteal progenitors might sense physical loading and trigger differentiation is unknown. We propose that periosteal osteochondroprogenitors (OCPs) directly sense mechanical load and differentiate into bone-forming osteoblasts via their primary cilia, mechanosensory organelles known to be involved in osteogenic differentiation. Methods We generated a diphtheria toxin ablation mouse model and performed ulnar loading and dynamic histomorphometry to quantify the contribution of periosteal OCPs in adult bone formation in vivo. We also generated a primary cilium knockout model and isolated periosteal cells to study the role of the cilium in periosteal OCP mechanosensing in vitro. Experimental groups were compared using one-way analysis of variance or student’s t test, and sample size was determined to achieve a minimum power of 80%. Results Mice without periosteal OCPs had severely attenuated mechanically induced bone formation and lacked the mineralization necessary for daily skeletal maintenance. Our in vitro results demonstrate that OCPs in the periosteum uniquely sense fluid shear and exhibit changes in osteogenic markers consistent with osteoblast differentiation; however, this response is essentially lost when the primary cilium is absent. Conclusions Combined, our data show that periosteal progenitors are a mechanosensitive cell source that significantly contribute to adult skeletal maintenance. More importantly, an OCP population persists in the adult skeleton and these cells, as well as their cilia, are promising targets for bone regeneration strategies.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adaptation / Adults / Aging / Animals / Biomedical and Life Sciences / Biomedical Engineering and Bioengineering / Bone and Bones - embryology / Bone growth / Bone histomorphometry / Bone marrow / Bone regeneration / Cell Biology / Cell Differentiation / Cellular signal transduction / Cilia / Diphtheria / Diphtheria toxin / Fluid flow / Fractures / Gene expression / Growth factors / Health aspects / Life Sciences / Load / Mechanical loading / Mechanical properties / Mechanical stimuli / Mechanotransduction / Mice / Mineralization / Organelles / Osteoblastogenesis / Osteoblasts / Osteoblasts - metabolism / Osteochondroprogenitors / Osteogenesis / Osteoprogenitor cells / Periosteal progenitors / Periosteum / Periosteum - metabolism / Primary cilium / Regeneration / Regenerative Medicine/Tissue Engineering / Rodents / Skeleton / Stem Cells / Stem Cells - cytology / Stem Cells - metabolism