A Novel Angiogenic Molecule Produced at the Time of Chondrocyte Hypertrophy during Endochondral Bone Formation

Abstract

Angiogenesis is a pivotal event in endochondral ossification. Vessels grow into the hypertrophic cartilage and erode it to produce a scaffold on which osteoblasts settle to produce woven bone. A new culture system was used to determine whether growth-plate chondrocytes produce an angiogenic molecule. Chondrocytes from primary growth plates of bovine fetuses were separated into maturationally distinct subpopulations. When cultured these cells produce an extensive extracellular matrix and the prehypertrophic cells mature to express the hypertrophic phenotype defined by the synthesis of type X collagen and matrix calcification. The culture medium collected from the hypertrophic cells contains a chemoattractant, nonmitogenic molecule for bovine endothelial cells which can induce angiogenesis in vivo in the rabbit cornea model. This molecule has a Mr of approximately 120 x 10(3). The production of this molecule by hypertrophic cells is enhanced by both 1,25-(OH)2 vitamin D3 and 24,25-(OH)2 vitamin D3 at 10(-8)-10(-12) M, but only in pre- and early hypertrophic cells. In contrast, these metabolites have either no effect or an inhibitory effect on the more mature hypertrophic cells. These results describe for the first time the production of an angiogenic molecule by hypertrophic chondrocytes. They demonstrate an important role for vitamin-D3 metabolites in regulating hypertrophy and angiogenesis during normal skeletal growth and differentiation. Thus, a defective regulation of these processes, due to the lack of vitamin-D metabolites, may explain the observed enlargement of the hypertrophic zone and impairment of skeletal growth in rickets which is induced clinically and experimentally by a deficiency of vitamin D.

CYR61, a product of a growth factor-inducible immediate early gene, promotes angiogenesis and tumor growth

“…These invasive trophoblasts help mediate nutrient exchange with maternal blood, and CYR61 expression in these cells may help to promote uterine vessel growth toward the embryo. During embryonic development, CYR61 is localized in hypertrophic cartilage (17), where vessel invasion produces conduits for osteoblasts to settle, leading to endochondral ossification (44). The presence of CYR61 may help to induce angiogenesis as a prelude to replacement of cartilage by bone.…”

Human chondrosarcoma secretes vascular endothelial growth factor to induce tumor angiogenesis and stores basic fibroblast growth factor for regulation of its own growth

“…the major angiogenic molecule released from hypertrophic chondrocytes and shown to promoted the migration of endothelial cells. 48 Alini et al 49 purified a novel angiogenic chemoattractant from bovine hypertrophic chondrocytes. The regulation, however, is disorganized in chondrosarcoma because of its oncogenicity.…”

Role of Growth Factors in the Development of Mandible

“…FGF-2 is one of the angiogenic factors produced by hypertrophied chondrocytes. 36 FGF-2 is also expressed in the proliferating and chondroblast layers of the adult rat's mandibular condyle. 37 FGF receptor expression is superficial in neonatal rat condyles but seems to extend deeper into the tissue at later ages.…”