Endothelial proteolytic activity and interaction with non-resorbing osteoclasts mediate bone elongation

Abstract

Growth plate cartilage contributes to the generation of a large variety in shapes and sizes of skeletal elements in the mammalian system. The removal of cartilage and how this process regulates bone shape are not well understood. Here we identify a non-bone-resorbing osteoclast subtype termed vessel associated osteoclast (VAO). Endothelial cells (ECs) at the bone-cartilage interface support VAOs through a RANKL-RANK signaling mechanism. Contrary to classical bone associated osteoclasts (BAOs), VAOs are dispensable for cartilage resorption and regulate anastomoses of type-H vessels. Remarkably, proteinases including Matrix metalloproteinase-9 (Mmp9) released from ECs, not osteoclasts, are essential for resorbing cartilage to lead directional bone growth. Importantly, disrupting the orientation of angiogenic blood vessels by misdirecting them results in contorted bone shape. This study identifies proteolytic functions of ECs in cartilage and provides a framework to explore tissue lytic features of blood vessels in fracture healing, arthritis and cancer.

Bone Vasculature and Bone Marrow Vascular Niches in Health and Disease

“…(87) Further, PDGFRβ + skeletal stem and progenitor cells (SSPCs) mainly reside in perivascular niches, and PDGF-PDGFRβ signaling induces SSPC proliferation, trafficking, and angiotropism during bone injury. (88) (106) ; Basic-Jukic and colleagues (147) BMP-4 ; Klimiuk and colleagues (142) ; Zimmermann-Geller and colleagues (143) FGF1 (60) ; Dias and colleagues (61) IL-33 Romeo and colleagues (39) Nidogen-1 ; Song and colleagues (38) Tenascin-C Romeo and colleagues (39) TNF-α Carlson and colleagues (182) Vascular roles of fibroblast growth factor Fibroblast growth factors (FGFs) are mainly secreted by bone lineage cells, including chondrocytes and osteoblasts, (89,90) and the receptors FGFR1 and FGFR2 expressed in vascular cells. (91) FGFs induces the expression of multiple angiogenic molecules, including VEGFA and VEGFR2, stimulating the growth of blood vessels and contributing to chondrocyte proliferation and the initiation of chondrocyte hypertrophy.…”

Spatial Distribution of Macrophages During Callus Formation and Maturation Reveals Close Crosstalk Between Macrophages and Newly Forming Vessels

“…Osteoblasts support the vasculature by producing VEGF and basic fibroblast growth factor (bFGF) while endothelial cells (ECs) provide factors that further osteoblast differentiation and activity (17). Furthermore, pre-osteoclasts and non-bone-resorbing osteoclasts have been described to enhance vascularization and osteogenesis in the growth plate area by releasing platelet-derived growth factor-BB (PDGF-BB) or supporting vessel anastomosis (18,19). While the production of angiogenic factors by osteoprogenitors is well-known, there is evidence accumulating that, conversely, endothelial cells can also impact on bone formation, at least during bone development (7).…”

Nuciferine prevents bone loss by disrupting multinucleated osteoclast formation and promoting type H vessel formation

“…Recently, researchers have demonstrated that type H vessels may have major effects on bone development and are mostly regulated by PDGF‐BB . Despite their limited quantity, many osteoprogenitor cells remain near type H vessels, and disruption of type H vessels can influence bone growth . Although complete inhibition of osteoclasts can reduce aging‐related bone loss, this strategy ignores the positive role of Trap + preosteoclasts in the coupling of osteogenesis and angiogenesis .…”

“…5,7,27 Angiogenesis plays an important role in sustaining the normal bone structure, and osteogenesis is based on the nutrient supply of blood vessels and requires molecular stimulation from endothelial cells. [1][2][3]28,29 The contribution of type H vessels to bone formation has been verified, [1][2][3]5,7,22,30,31 and its quantity is relevant to bone mass. 8 Although we proved that NCF could inhibit osteoclast formation and increase the quantity of Trap + preosteoclasts, the influence of NCF on the function of endothelial cells and the formation of type H vessels was not clear.…”

“…5 Despite their limited quantity, many osteoprogenitor cells remain near type H vessels, and disruption of type H vessels can influence bone growth. 1,22 Although complete inhibition of osteoclasts can reduce aging-related bone loss, this strategy ignores the positive role of Trap + preosteoclasts in the coupling of osteogenesis and angiogenesis. 5 Trap + preosteoclasts can secrete high levels of PDGF-BB and promote type H vessel formation, and some studies have shown that PDGF-BB treatment or a genetic increase in Trap + preosteoclasts can prevent OVXinduced osteoporosis.…”