RESEARCH HIGHLIGHTS Nature Reviews Endocrinology 10, 250 (2014); published online 18 March 2014; doi:10.1038/nrendo.2014.28
BONE
Formation of blood vessels in bone maturation and regeneration Two studies published in Nature reveal that a particular type of blood vessel and an associated signalling pathway are involved in bone growth. The authors of the studies note that previous evidence has indicated a connection between the growth of blood vessels in bone and osteogenesis, but understanding of the underlying cellular and molecular mechanisms was limited. Ralf Adams and co-workers have now attempted to fill in this gap. In the first study, Adams and colleagues used wild-type mice and mice with mutations specific to endothelial cells to visualise the microvascular structure in bone. Imaging using immunofluorescence showed that this microvascular structure contained two distinct subtypes of capillaries (CD31hi/Emcnhi and CD31lo/ Emcnlo). After analysis of other organs, the researchers found that the CD31hi/ Emcnhi subset was almost unique to bone (it was also identified in liver samples). Osteoblasts and osteocytes were found to be selectively positioned around CD31hi/ Emcnhi endothelial cells, and not around CD31lo/Emcnlo endothelial cells. The researchers also found that aged mice have much lower levels of CD31hi/ Emcnhi endothelial cells than juvenile mice. “The decline of CD31hi/Emcnhi vessels and the concomitant reduction of osteoprogenitor cells could potentially offer a compelling explanation for the loss of bone mass during ageing and might enable
Vascular front in proximal mouse tibia (long bone) showing bulbs and arches. Nuclear staining (DAPI) in blue and CD31 staining in red. Courtesy of MPI Muenster/Saravana K. Ramasamy.
therapeutic improvement of osteogenesis in elderly people,” write the authors. In the second study, Adams and his team investigated how blood vessels grow in bones. They found that, in mice, Notch signalling promoted the proliferation of endothelial cells and the growth of blood vessels in bones. These findings are in contrast to the established function of Notch signalling in other organs. The researchers generated genetically modified mice with disrupted Notch signalling in endothelial cells. These mice displayed impaired blood vessel growth and morphology in bone, as well as reduced osteogenesis, shortening of long bones, chondrocyte defects, loss of trabeculae and decreased bone mass. These mice were also found to have defective release of Noggin (which is
NATURE REVIEWS | ENDOCRINOLOGY
positively regulated by Notch) from endothelial cells. When recombinant Noggin was administered to the mutant mice, the bone defects described above were largely reversed, which suggests that this signalling pathway is involved in the formation of the skeletal defects. “These findings establish a molecular framework coupling angiogenesis, angiocrine signals and osteogenesis, which may prove significant for the development of future therapeutic applications,” conclude the authors. Claire Greenhill Original articles Adams, R. et al. Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone. Nature doi:10.1038/nature13145 | Adams, R. et al. Endothelial Notch activity promotes angiogenesis and osteogenesis in bone. Nature doi:10.1038/nature13146
VOLUME 10 | MAY 2014 © 2014 Macmillan Publishers Limited. All rights reserved
BONE
Formation of blood vessels in bone maturation and regeneration Two studies published in Nature reveal that a particular type of blood vessel and an associated signalling pathway are involved in bone growth. The authors of the studies note that previous evidence has indicated a connection between the growth of blood vessels in bone and osteogenesis, but understanding of the underlying cellular and molecular mechanisms was limited. Ralf Adams and co-workers have now attempted to fill in this gap. In the first study, Adams and colleagues used wild-type mice and mice with mutations specific to endothelial cells to visualise the microvascular structure in bone. Imaging using immunofluorescence showed that this microvascular structure contained two distinct subtypes of capillaries (CD31hi/Emcnhi and CD31lo/ Emcnlo). After analysis of other organs, the researchers found that the CD31hi/ Emcnhi subset was almost unique to bone (it was also identified in liver samples). Osteoblasts and osteocytes were found to be selectively positioned around CD31hi/ Emcnhi endothelial cells, and not around CD31lo/Emcnlo endothelial cells. The researchers also found that aged mice have much lower levels of CD31hi/ Emcnhi endothelial cells than juvenile mice. “The decline of CD31hi/Emcnhi vessels and the concomitant reduction of osteoprogenitor cells could potentially offer a compelling explanation for the loss of bone mass during ageing and might enable
Vascular front in proximal mouse tibia (long bone) showing bulbs and arches. Nuclear staining (DAPI) in blue and CD31 staining in red. Courtesy of MPI Muenster/Saravana K. Ramasamy.
therapeutic improvement of osteogenesis in elderly people,” write the authors. In the second study, Adams and his team investigated how blood vessels grow in bones. They found that, in mice, Notch signalling promoted the proliferation of endothelial cells and the growth of blood vessels in bones. These findings are in contrast to the established function of Notch signalling in other organs. The researchers generated genetically modified mice with disrupted Notch signalling in endothelial cells. These mice displayed impaired blood vessel growth and morphology in bone, as well as reduced osteogenesis, shortening of long bones, chondrocyte defects, loss of trabeculae and decreased bone mass. These mice were also found to have defective release of Noggin (which is
NATURE REVIEWS | ENDOCRINOLOGY
positively regulated by Notch) from endothelial cells. When recombinant Noggin was administered to the mutant mice, the bone defects described above were largely reversed, which suggests that this signalling pathway is involved in the formation of the skeletal defects. “These findings establish a molecular framework coupling angiogenesis, angiocrine signals and osteogenesis, which may prove significant for the development of future therapeutic applications,” conclude the authors. Claire Greenhill Original articles Adams, R. et al. Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone. Nature doi:10.1038/nature13145 | Adams, R. et al. Endothelial Notch activity promotes angiogenesis and osteogenesis in bone. Nature doi:10.1038/nature13146
VOLUME 10 | MAY 2014 © 2014 Macmillan Publishers Limited. All rights reserved
