Macrophages: Their Emerging Roles in Bone

Abstract

Macrophages are present in nearly all tissues and are critical for development, homeostasis, and regeneration. Resident tissue macrophages of bone, termed osteal macrophages, are recently classified myeloid cells that are distinct from osteoclasts. Osteal macrophages are located immediately adjacent to osteoblasts, regulate bone formation, and play diverse roles in skeletal homeostasis. Genetic or pharmacological modulation of macrophages in vivo results in significant bone phenotypes, and these phenotypes depend on which macrophage subsets are altered. Macrophages are also key mediators of osseous wound healing and fracture repair, with distinct roles at various stages of the repair process. A central function of macrophages is their phagocytic ability. Each day, billions of cells die in the body and efferocytosis (phagocytosis of apoptotic cells) is a critical process in both clearing dead cells and recruitment of replacement progenitor cells to maintain homeostasis. Recent data suggest a role for efferocytosis in bone biology and these new mechanisms are outlined. Finally, although macrophages have an established role in primary tumors, emerging evidence suggests that macrophages in bone support cancers which preferentially metastasize to the skeleton. Collectively, this developing area of osteoimmunology raises new questions and promises to provide novel insights into pathophysiologic conditions as well as therapeutic and regenerative approaches vital for skeletal health.

Osteoimmunology and Beyond

“…A central function of macrophages is their phagocytic ability. In particular, efferocytosis (phagocytosis of apoptotic cells) is a critical process in both clearing dead cells and replacement of progenitor cells to maintain bone homeostasis [45]. …”

“…Osteal macrophages expressing CD68, a phagocytic capacity marker of cells infiltrating metastatic lesions, could facilitate tumor establishment and growth. Tumor-derived PTHrP drives myeloid cell recruitment via OB produced CCL2, which is high in the bone microenvironment and whose levels are associated with poor prognoses in primary breast tumors [45]. …”

Macrophages and skeletal health

“…The bone and bone marrow consist of several other cells that play crucial supportive roles in the process of homeostatic bone turnover including, but not limited to, T and B cells, mast cells, and monocytes/macrophages (Chang, et al, 2008; Frame & Nixon, 1968; Y. Li, et al, 2007; Sinder, et al, 2015; Xiao, et al, 2016). An imbalance in the bone remodeling process due to alterations in osteoblast or osteoclast activity can lead to elevated bone mass (increased osteoblast activity or decreased osteoclast activity) or decreased bone mass (decreased osteoblast activity or increased osteoclast activity).…”

Cell communication modes and bidirectional mitochondrial exchange in direct and indirect macrophage/hMSC co-culture models

“…They reflect immune-modulatory properties, as they secrete chemotactic peptides and can change the macrophage phenotype into an anti-inflammatory M2-like type [5], [6], [7], [8]. Furthermore, their stimulatory effect on phagocytic activity, a main characteristic of macrophages, has been reported [8].…”

“…Upon tissue injury, both hMSCs and macrophages display several roles in the inflammatory and regenerative phases of healing as well as in the remodeling phases, during which tissue regeneration takes place. In the very early phase of bone healing resident macrophages have even been demonstrated to be involved in efferocytosis, the removal of dying osteoblasts [5], [6]. Besides neutrophils and mast cells, such tissue resident macrophages belong to the first cells that enter the wound site.…”