Two macrophages, osteoclasts and microglia: from development to pleiotropy

Abstract

Tissue-resident macrophages are highly specialized to their tissue-specific microenvironments, activated by various inflammatory signals and modulated by genetic and environmental factors. Osteoclasts and microglia are distinct tissue-resident cells of the macrophage lineage in bone and brain that are responsible for pathological changes in osteoporosis and Alzheimer's disease (AD), respectively. Osteoporosis is more frequently observed in individuals with AD compared to the prevalence in general population. Diagnosis of AD is often delayed until underlying pathophysiological changes progress and cause irreversible damages in structure and function of brain. As such earlier diagnosis and intervention of individuals at higher risk would be indispensable to modify clinical courses. Pleiotropy is the phenomenon that a genetic variant affects multiple traits and the genetic correlation between two traits could suggest a shared molecular mechanism. In this review, we discuss that the Pyk2-mediated actin polymerization pathway in osteoclasts and microglia in bone and brain, respectively, is the horizontal pleiotropic mediator of shared risk factors for osteoporosis and AD.

Fig. 1

Developmental overview and homeostasis regulations of osteoclasts and microglia. Primitive macrophages exit blood islands of the yolk sac (YS) with the initiation of circulation and colonized the neuroepithelium from E8.5 to give rise to microglia. In a steady state, YS-derived macrophages are differentiated into microglia which, in turn, self-renew throughout ontogeny until adulthood. Under pathological conditions, circulating progenitors or resident macrophages that are allowed to reside in brain contribute to newly differentiated microglia. The migration of definitive brain macrophage is initiated from the HSCs of the embryonic aorta-gonad-mesonephros (AGM). Subsequently, HSCs expand in the fetal liver, which is the main source for tissue-specific macrophages. Osteoclasts originated from resident embryonic-myeloid progenitors (EMPs) lineage, which are long-lived and can participate in postnatal bone maintenance. Adult bone homeostasis is maintained by osteoclast fusion that are derived from EMPs and HSCs supplied by bone marrow and possibly by spleen. In injured skeletal tissues, for instance due to bone fracture, circulating monocytes and macrophages from spleen migrate into damaged tissue and contribute to tissue repairing

Fig. 2

TREM2/DAP12-, CSF1/CSF1R-, and CCR5 pathways in osteoclasts and microglia. Once ligands bind to TREM2, two tyrosine residues in the immunoreceptor tyrosine-based activation motif (ITAM) of DAP12 are phosphorylated, which in turn recruits Syk kinase to activate downstream molecules such as Src tyrosine kinase and phosphatidylinositol 3-kinase (PI3K). The soluble form of TREM2 (sTREM2) is generated by ɣ-secretase, which activates PI3K, extracellular signal-regulated protein kinase (ERK), and NF-kB. Src, the main effector of CSF1R, is a tyrosine kinase that phosphorylates the ITAM tyrosine residues. CCL3/4/5 binding to CCR5 activates G protein and multiple downstream signals such as Src, PLC-ɣ and PI3K. PI3K triggers the tyrosine phosphorylation of focal adhesion complex components such as Pyk2, paxillin, Crk, and p130Cas, leading to interaction with Vav. Pyk2-Vav interaction may control Rho family GTPase activation, thereby driving localized actin polymerization that stabilizes contacts with matrix and/or promote migration

Fig. 3

Horizontal pleiotropy of common genetic factors. Pyk2 signal could be a converging pathway of the genetic correlation between osteoporosis and Alzheimer’s disease (AD). Genetic variants in PTK2B are significantly associated with AD, body mass index, and bone mineral density suggesting that the two traits—osteoporosis and AD—could be linked by horizontal pleiotropy