Periosteal CD68+ F4/80+ Macrophages Are Mechanosensitive for Cortical Bone Formation by Secretion and Activation of TGF-β1

Abstract

Mechanical force regulates bone density, modeling, and homeostasis. Substantial periosteal bone formation is generated by external mechanical stimuli, yet its mechanism is poorly understood. Here, it is shown that myeloid-lineage cells differentiate into subgroups and regulate periosteal bone formation in response to mechanical loading. Mechanical loading on tibiae significantly increases the number of periosteal myeloid-lineage cells and the levels of active transforming growth factor β (TGF-β), resulting in cortical bone formation. Knockout of Tgfb1 in myeloid-lineage cells attenuates mechanical loading-induced periosteal bone formation in mice. Moreover, CD68⁺ F4/80⁺ macrophages, a subtype of myeloid-lineage cells, express and activate TGF-β1 for recruitment of osteoprogenitors. Particularly, mechanical loading induces the differentiation of periosteal CD68⁺ F4/80^- myeloid-lineage cells to the CD68⁺ F4/80⁺ macrophages via signaling of piezo-type mechanosensitive ion channel component 1 (Piezo1) for TGF-β1 secretion. Importantly, CD68⁺ F4/80⁺ macrophages activate TGF-β1 by expression and secretion of thrombospondin-1 (Thbs1). Administration of Thbs1 inhibitor significantly impairs loading-induced TGF-β activation and recruitment of osteoprogenitors in the periosteum. The results suggest that periosteal myeloid-lineage cells respond to mechanical forces and consequently produce and activate TGF-β1 for periosteal bone formation.

Keywords: cortical bone formation; macrophage; mechanical loading; periosteum.