Regulation of Periosteal Myeloid-Lineage Cells for Cortical Bone Formation

Abstract

Cortical bone mass determines bone strength and fracture resistance, which is mediated by the periosteum. Periosteal bone formation decreases with age but can be stimulated and revived by mechanical loading. Yet the mechanism that regulates cortical bone homeostasis and loading-induced periosteal bone formation has not been fully understood. This dissertation uncovered the underlying cellular and molecular mechanisms of cortical bone formation. Chapter 1 provides a broad introduction of periosteal bone formation to the field of what has been known. In Chapter 2 and Chapter 3, two distinct subpopulations of myeloid-lineage cells, tartrate-resistant acid phosphatase–positive (TRAP+) and CD68+F4/80+, have been identified in the periosteum. We have found that periosteal TRAP+ mononuclear cells secrete platelet-derived growth factor-BB (PDGF-BB), which sequentially recruits periosteum-derived cells (PDCs) to the periosteal bone surface. The recruited PDCs differentiate into osteoblasts coupled with angiogenesis to maintain the cortical bone homeostasis. We specifically deleted Pdgfb in TRAP+ cells using a Trap-cre;Pdgfbf/f mouse model. Significant declines in periosteal bone formation with impaired PDC recruitment and periostin expression were noted in the knockout mice. Consistent with these findings, the knockout of PDGF receptor β also showed a remarkable decrease of PDCs on the periosteal bone surface. Based on these observations, we explored the regulation of myeloid-lineage cells in mechanical loading-induced periosteal bone formation. Surprisingly, mechanical loading did not induce significant changes in the number of periosteal TRAP+ cells as expected. Another subpopulation of periosteal myeloid-lineage cells, CD68+F4/80+ but TRAP-, was found to be increased after mechanical loading. Mechanistically, mechanical loading induced the differentiation of CD68+F4/80- into CD68+F4/80+ macrophages through piezo-type mechanosensitive ion channel component 1 (PIEZO1) signaling. CD68+F4/80+ macrophages secrete and further activate TGF-β1 via thrombospondin-1 (Thbs1) to recruit osteoprogenitors to the periosteal bone surface for cortical bone formation. Knockout of Tgfb1 in myeloid-lineage cells attenuated mechanical loading-induced periosteal bone formation in mice. Administration of Thbs1 inhibitor significantly impaired loading-induced TGF-β activation and recruitment of osteoprogenitors in the periosteum. In conclusion, this dissertation has distilled the essential role of periosteal myeloid-lineage cells in regulating PDCs or osteoprogenitors for cortical bone homeostasis and loading-induced cortical bone formation