Macrophages Promote Osteoblastic Differentiation In Vivo: Implications in Fracture Repair and Bone Homeostasis

Abstract

Macrophages are activated in inflammation and during early phases of repair processes. Interestingly, they are also present in bone during development, but their function during this process is unclear. Here, we explore the function of macrophages in bone development, growth, and repair using transgenic mice to constitutively or conditionally deplete macrophages. Depletion of macrophages led to early skeletal growth retardation and progressive osteoporosis. By 3 months of age, macrophage-deficient mice displayed a 25% reduction in bone mineral density and a 70% reduction in the number of trabecular bone compared to control littermates. Despite depletion of macrophages, functional osteoclasts were still present in bones, lining trabecular bone and the endosteal surface of the cortical bone. Furthermore, ablation of macrophages led to a 60% reduction in the number of bone marrow mesenchymal progenitor cells and a decrease in the ability of these cells to differentiate to osteoblasts. When macrophages were depleted during fracture repair, bone union was impaired. Calluses from macrophage-deficient animals were smaller, and contained less bone and more fibrotic tissue deposition. Taken together, this shows that macrophages are crucial for maintaining bone homeostasis and promoting fracture repair by enhancing the differentiation of mesenchymal progenitors.

Snapshot: Targeting Macrophages as a Candidate for Tissue Regeneration

“…This finding is concurrent with the in vitro experiment indicating that the removal of macrophages diminished osteoblast mineralization (Chang et al, 2008). This decreased mineralization is probably associated with the lack of osteoblasts originated from macrophage-enhanced osteoblastic differentiation (Vi et al, 2015). Claudia et al have proven that M2 macrophage enhancement driven by IL-4 and IL-13 improved bone remodeling (Schlundt et al, 2015).…”

NPY and CGRP Inhibitor Influence on ERK Pathway and Macrophage Aggregation during Fracture Healing

“…It has been reported that macrophages can convert to a pro-healing phenotype and promote limb generation [17]. Macrophages could also help maintain bone homeostasis and promote fracture healing by enhancing the differentiation process of mesenchymal progenitors [2]. Herein we inferred that macrophage aggregation would likely present in the femoral fracture area.…”

Metaphyseal Fracture Healing

“…Further experiments are required to clarify this. A time sensitive effect was reported also in a shaft model where reduced macrophage numbers before the time of fracture had a stronger effect than if the reduction occurred 3 days after [51]. Similarly in a water salamander model where a foot was resected; regrowth of the limb was blocked permanently if clodronate liposomes were delivered before the surgery but not if the liposomes were injected at day 10 to 13.…”