Monocyte/Macrophage Lineage Cells From Fetal Erythromyeloid Progenitors Orchestrate Bone Remodeling and Repair

Abstract

A third of the population sustains a bone fracture, and the pace of fracture healing slows with age. The slower pace of repair is responsible for the increased morbidity in older individuals who sustain a fracture. Bone healing progresses through overlapping phases, initiated by cells of the monocyte/macrophage lineage. The repair process ends with remodeling. This last phase is controlled by osteoclasts, which are bone-specific multinucleated cells also of the monocyte/macrophage lineage. The slower rate of healing in aging can be rejuvenated by macrophages from young animals, and secreted proteins from macrophage regulate undifferentiated mesenchymal cells to become bone-forming osteoblasts. Macrophages can derive from fetal erythromyeloid progenitors or from adult hematopoietic progenitors. Recent studies show that fetal erythromyeloid progenitors are responsible for the osteoclasts that form the space in bone for hematopoiesis and the fetal osteoclast precursors reside in the spleen postnatally, traveling through the blood to participate in fracture repair. Differences in secreted proteins between macrophages from old and young animals regulate the efficiency of osteoblast differentiation from undifferentiated mesenchymal precursor cells. Interestingly, during the remodeling phase osteoclasts can form from the fusion between monocyte/macrophage lineage cells from the fetal and postnatal precursor populations. Data from single cell RNA sequencing identifies specific markers for populations derived from the different precursor populations, a finding that can be used in future studies. Here, we review the diversity of macrophages and osteoclasts, and discuss recent finding about their developmental origin and functions, which provides novel insights into their roles in bone homeostasis and repair.

Preventive CCL2/CCR2 Axis Blockade Suppresses Osteoclast Activity in a Mouse Model of Rheumatoid Arthritis by Reducing Homing of CCR2hi Osteoclast Progenitors to the Affected Bone

“…Recent literature strongly evidenced that circulating cells are a source of OCPs, especially in conditions that perturb the integrity of the bone marrow microenvironment ( 9 , 12 ). Therefore, we further dissected peripheral and periarticular OCP subsets among the myeloid non-granulocyte (Ly6G - ) population, and assessed the expression of CCR2 and CX3CR1 receptors that potentially mediate chemoattraction ( Figure 2A ).…”

“…The current concept suggests that osteoclasts arise from two sources of progenitors, the embryonic yolk sac-derived erythromyeloid extramedullar progenitors and hematopoietic stem cell-derived myeloid progenitors ( 8 ). Furthermore, the data from cell-fate analyses indicated the possibility of cell–cell fusion between these two lineages ( 9 ). During inflammation-induced bone resorption, there is an established osteoclast activity in places far from the hematopoietically active bone marrow.…”

“…A recent review by Yahara et al. suggests that additional studies are needed to reveal the mechanisms that orchestrate the mobilization of circulating OCPs from the extramedullary organs to bone in pathologic or homeostatic conditions ( 9 ).…”

“…However, it remains unclear whether osteoclasts derive predominantly from circulating monocytes or bone marrowresident progenitors (12). A recent review by Yahara et al suggests that additional studies are needed to reveal the mechanisms that orchestrate the mobilization of circulating OCPs from the extramedullary organs to bone in pathologic or homeostatic conditions (9).…”

Developmental Origins of Metaflammation; A Bridge to the Future Between the DOHaD Theory and Evolutionary Biology

“…Previous studies suggested the commitment of erythro-myeloid progenitors produced in the extra-embryonic yolk sac to the establishment of long-lasting immunological memory (36,(46)(47)(48). Yahara et al proposed the involvement of erythro-myeloid progenitors in bone regeneration after birth (49). Wu et al also reported the potential contribution of erythro-myeloid progenitors to homeostasis after birth (50).…”