Skeleton-vasculature chain reaction: a novel insight into the mystery of homeostasis

Abstract

Angiogenesis and osteogenesis are coupled. However, the cellular and molecular regulation of these processes remains to be further investigated. Both tissues have recently been recognized as endocrine organs, which has stimulated research interest in the screening and functional identification of novel paracrine factors from both tissues. This review aims to elaborate on the novelty and significance of endocrine regulatory loops between bone and the vasculature. In addition, research progress related to the bone vasculature, vessel-related skeletal diseases, pathological conditions, and angiogenesis-targeted therapeutic strategies are also summarized. With respect to future perspectives, new techniques such as single-cell sequencing, which can be used to show the cellular diversity and plasticity of both tissues, are facilitating progress in this field. Moreover, extracellular vesicle-mediated nuclear acid communication deserves further investigation. In conclusion, a deeper understanding of the cellular and molecular regulation of angiogenesis and osteogenesis coupling may offer an opportunity to identify new therapeutic targets.

Fig. 1

Novel concepts related to the bone vasculature. Transcortical vessels (TCVs) are important vascular structures that originate in the bone marrow and traverse cortical bone canals perpendicularly along the bone shaft, eventually joining the direct periosteal circulation. Over 80% of the arterial blood stream and 59% of the venous blood flow passes through TCVs. TCVs located across the narrow canals of cortical bone provide an orientation for immune cells and hematopoietic stem cells (HSCs) to migrate from the bone marrow to the general outer peripheral circulation and help mediate highly effective blood exchange between the microvasculature in the internal and external circulation

Fig. 2

Endothelial cell heterogeneity of bone vessels. Distinct capillary subsets with high heterogeneity in the skeletal system can be subdivided into type H and type L endothelium based on morphology, specialization, molecular identity, and functional properties. Type H vessels are primarily distributed around the endosteum region and metaphysis close to the growth plate. They are linearly arranged with distinctive columnar structures and interconnected with new anastomotic loop-like arches at the distal edge. Type L vessels are located with highly branched networks in the bone marrow region of the diaphysis. Type H capillaries are selectively surrounded by Runx2⁺, collagen 1α⁺, and Osterix-expressing osteoprogenitors, as well as PDGFRβ- and NG2-expressing perivascular cells. Type L capillaries are predominantly infiltrated by PDGFRα- and LEPR-positive cells as well as CAR cells, which interact with HSCs in the regulation of hematopoiesis. Arteries branch into smaller arterioles and flow into type H vessels in the region of the metaphysis near the growth plate. They then converge into a type L sinusoid network at the interface of the diaphysis and are terminally drained via veins located in the contiguous medullary region