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Macrophage–H-type endothelial cell crosstalk in osteoporotic osteal immunity: Molecular mechanisms and Bone Tissue Engineering Interventions

bioengineering
geriatrics
orthopedics

Abstract

Communication between macrophages (MΦs) and type H endothelial cells (ECs) plays a pivotal role in restoring osteogenic–angiogenic coupling and maintaining bone homeostasis during osteoporosis (OP). Type H vessels (CD31 hi Emcn hi ), owing to their unique functional properties, offer new insights into the vascular regulation of bone metabolism. Their discovery has shifted the paradigm of bone research from a “bone-centered” to a “vasculature–bone integrated” framework, thereby advancing our understanding of angiogenic–osteogenic coupling. As highly heterogeneous innate immune cells, MΦs undergo polarization in response to conditions such as ischemia and hypoxia, estrogen deficiency, and aging. These changes modulate osteogenic–angiogenic coupling and provide potential targets for improving bone quality in OP. In recent years, the spatiotemporal interplay between ECs and MΦs has been increasingly recognized as a key factor in angiogenesis–osteogenesis coupling and bone repair. The coordinated organization of the type H vascular niche and bone immunity offers new avenues for restoring bone homeostasis in osteoporosis. However, the mechanistic basis of their communication in regulating angiogenic–osteogenic coupling remains poorly understood, and supporting clinical evidence is still limited. Therefore, this review provides a comprehensive overview of the communication patterns and signaling pathways between MΦs of different phenotypes and H-type ECs within the bone microenvironment during osteoporotic bone regeneration and remodeling. It further elucidates how upstream regulatory factors—such as peripheral nerves, mechanical stress, and ionic homeostasis—modulate their crosstalk. By exploring these mechanisms, we aim to shed light on the cellular communication underlying angiogenic–osteogenic coupling in bone healing and regeneration. In addition, we discuss emerging therapeutic strategies, including bone tissue engineering and bone organoids, that enable precise modulation of MΦ–EC interactions, offering new perspectives and potential avenues for the clinical management of OP.
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