Exosomes in bone health and disease: cellular crosstalk, systemic signaling, and AI-driven advances in regenerative therapy

Abstract

Exosomes have emerged as critical mediators of intercellular and inter-organ communication in bone biology. Secreted by bone-resident cells such as osteoblasts, osteoclasts, osteocytes, and mesenchymal stem cells (MSCs), these nanosized vesicles carry diverse molecular cargos that regulate bone remodeling, regeneration, and skeletal homeostasis. In addition to mediating local communication within the bone microenvironment, exosomes also participate in systemic crosstalk communication between bone and other tissues, including skeletal muscle, adipose tissue, gut microbiota, the immune system, the nervous system, and vasculature. Disruption of these exosome-mediated pathways contributes to the development and progression of bone diseases, including osteoporosis, osteoarthritis, osteonecrosis of the femoral head, and bone metastases. This review summarizes current advances in exosome-mediated signaling in both physiological and pathological contexts, with particular emphasis on their roles as biomarkers, therapeutic agents, and drug delivery vehicles. We also discuss the emerging contribution of artificial intelligence (AI) to exosome research, especially in biomarker discovery, disease classification, and target identification, as well as the major challenges that currently limit clinical translation. Together, these insights highlight the potential of exosome-based strategies for precision medicine in bone diseases.

1. Introduction

Bone diseases—including osteoporosis, osteoarthritis, and osteonecrosis of the femoral head (ONFH)—represent major global public health concerns due to their high morbidity and associated disability rates [1, 2]. The onset and progression of these conditions are closely linked to imbalances in bone metabolism and structural damage, with alterations in the bone microenvironment playing a central role. Traditionally recognized for its structural and metabolic functions, the bone has more recently been redefined as an endocrine organ capable of active communication with other tissues. The bone microenvironment is a complex, dynamic system composed of various cellular and stromal components, including osteoblasts, osteoclasts, mesenchymal stem cells (MSCs), adipocytes, matrix proteins, vasculature [3–6].

While intercellular communication within this microenvironment has long been attributed to direct cell-to-cell contact and soluble signaling molecules, emerging evidence highlights the critical role of exosomes as novel mediators of cellular crosstalk [7]. Exosomes are small membrane-bound extracellular vesicles (EVs), approximately 30–150 nm in diameter, secreted by multiple cell types—including osteoblasts, osteoclasts, MSCs, and immune cells—and are present in various body fluids and tissues [2, 8–10]. Enclosed by a phospholipid bilayer, they carry diverse bioactive molecules such as nucleic acids, proteins, and lipids [11].

In bone biology, exosome-mediated communication has attracted increasing attention because it links intra-skeletal regulation with systemic inter-organ signaling. Exosomes derived from bone-resident cells influence osteogenesis, osteoclastogenesis, angiogenesis, and immune responses, while exosomal signals from other tissues, such as skeletal muscle, adipose tissue, the gut microbiota, and immune systems, can in turn reshape bone homeostasis and disease progression.