news and views
npg
© 2014 Nature America, Inc. All rights reserved.
inhibition of AEP could have multiple benefits, by reducing cleavage of tau and decreasing tau phosphorylation in part by the reduced processing of PP2AI10. However, potential AEP inhibitors would need a high substrate specificity for tau and PPA2I for therapeutic applications in order to avoid undesired side effects. Another important consideration is whether an AEP targeting strategy would be suitable only in patients with high AEP activity or for more general use in AD10. It will also be important to explore whether such therapy would be more effective for preventive purposes in healthy or presymptomatic individuals. As AEP levels are increased in aging mice, aged individuals may be good candidates for this treatment approach to prevent tau dysfunction.
This study provides evidence for the direct cleavage of tau by AEP and suggests links between different pathogenic hallmarks in AD, including the enhancement of AEP cleavage of tau by amyloid-β and facilitation of tau phosphorylation through its truncation by AEP. The central role of AEP activity in tau pathology makes this enzyme an attractive therapeutic target for AD and other neurodegenerative disorders associated with neurofibrillary tangles. COMPETING FINANCIAL INTERESTS The author declares no competing financial interests. 1. Arriagada, P.V., Growdon, J.H., Hedley-Whyte, E.T. & Hyman, B.T. Neurology 42, 631–639 (1992). 2. Ballatore, C., Lee, V.M. & Trojanowski, J.Q. Nat. Rev. Neurosci. 8, 663–672 (2007).
3. Avila, J., Lucas, J.J., Perez, M. & Hernandez, F. Physiol. Rev. 84, 361–384 (2004). 4. Mandelkow, E.M. & Mandelkow, E. Cold Spring Harb. Perspect. Med. 2, a006247 (2012). 5. Binder, L.I., Guillozet-Bongaarts, A.L., Garcia-Sierra, F. & Berry, R.W. Biochim. Biophys. Acta 1739, 216–223 (2005). 6. Wang, Y., Garg, S., Mandelkow, E.M. & Mandelkow, E. Biochem. Soc. Trans. 38, 955–961 (2010). 7. Zhang, Z. et al. Nat. Med. 20, 1254–1262 (2014). 8. Liu, Z. et al. Mol. Cell 29, 665–678 (2008). 9. Herskowitz, J.H. et al. Proteomics 12, 2455–2463 (2012). 10. Basurto-Islas, G., Grundke-Iqbal, I., Tung, Y.C., Liu, F. & Iqbal, K. J. Biol. Chem. 288, 17495–17507 (2013). 11. Rapoport, M., Dawson, H.N., Binder, L.I., Vitek, M.P. & Ferreira, A. Proc. Natl. Acad. Sci. USA 99, 6364–6369 (2002). 12. Park, S.Y. & Ferreira, A. J. Neurosci. 25, 5365–5375 (2005). 13. Kayed, R. et al. Science 300, 486–489 (2003). 14. Clavaguera, F. et al. Brain Pathol. 23, 342–349 (2013). 15. Nakamura, Y. et al. Neurosci. Lett. 130, 195–198 (1991).
Osteoclast progenitors promote bone vascularization and osteogenesis Anjali P Kusumbe & Ralf H Adams Preosteoclasts give rise to bone-resorbing osteoclasts, which are crucial for skeletal homeostasis. A study now shows that preosteoclasts also contribute to bone formation by releasing platelet-derived growth factor-BB, which promotes bone vascularization and osteogenesis. The skeleton is a dynamic tissue, and its lifelong maintenance relies on the balance of two ongoing processes. Bone is resorbed by osteoclasts, which are phagocytic cells generated by the fusion of monocytes, and new bone is generated by osteoblasts. Osteoblasts are derived from osteoprogenitors, which, in turn, are formed by self-renewing mesenchymal stem cells (MSCs). During bone fracture repair, osteoprogenitors invade the lesioned area together with growing blood vessels1. Increasing evidence indicates that blood vessel growth not only establishes local circulation in the newly formed bone, and thereby access to nutrients and oxygen, but also directly promotes bone formation1–3. In particular, a subset of capillaries expressing high levels of the markers CD31 and endomucin (termed CD31hiEmcnhi or type H) has recently been shown to drive postnatal angiogenesis in the skeletal system and promote Anjali P. Kusumbe and Ralf H. Adams are at the Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, and in the Faculty of Medicine, University of Münster, Münster, Germany. e-mail: [email protected]
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osteogenesis through the release of secreted factors2,3. However, the molecular cross talk between different cell populations in the skeletal system is not fully understood. In this issue of Nature Medicine, Xie et al.4 now show that preosteoclasts (POCs), the immature progenitors of bone-degrading osteoclasts, enhance angiogenesis and osteogenesis during bone remodeling through the release of platelet-derived growth factor-B. The authors of the study refer to it as PDGF-BB, the homodimeric form of the growth factor. They began by investigating the role of osteoclast-lineage cells in periosteal bone formation using mice lacking the gene encoding cytokine colony stimulating factor-1 (Csf), which is essential for the survival of cells in the monocyte/ macrophage lineage. This leads to the absence of osteoclasts and their progenitors. The authors found that Csf1−/− mice had thin cortical bones and decreased bone vascularization. To investigate whether these defects were caused by a loss of signals secreted by POCs or osteoclasts, the authors collected supernatants from these cells in culture and analyzed their effect on MSC migration. Supernatant from POCs increased MSC migration,
whereas supernatant from osteoclasts had no effect. Using a systematic approach involving neutralizing antibodies targeting various candidate molecules, the authors identified PDGF-BB, but not the related growth factor homodimer PDGF-AA, as a POC-secreted factor contributing to MSC migration. This supported previous findings that PDGF-BB is released by immature and nonresorbing osteoclasts5,6. PDGF-BB is mitogenic and chemotactic and promotes the proliferation and migration of many different mesenchymal cell types such as MSCs, pericytes and fibroblasts7. These cell types express the PDGF-BB receptor PDGFR-β, which can trigger a range of signal transduction processes including the mitogenactivated kinase and phosphoinositide3 kinase–Akt cascades. Mice lacking the Pdgfb gene in all cells die shortly after birth due to hemorrhaging and kidney defects. Xie et al.4 have now used the Cre-loxP approach to inactivate Pdgfb specifically in osteoclastlineage cells. This confirmed that the osteoclast lineage is a major source of PDGF-BB in peripheral blood and bone marrow. Moreover, trabecular bone mass, cortical
volume 20 | number 11 | november 2014 nature medicine
news and views
Bone degradation
Osteoprogenitors Bone formation
Osteoclasts
npg
© 2014 Nature America, Inc. All rights reserved.
Katie Vicari/Nature Publishing Group
Bone vascularization CTSK inhibitor
Osteoblasts ?
Differentiation ↑Migration ↑Proliferation
Accumulation of POCs
POCs
↑Migration ↑Proliferation
Mesenchymal Type H ECs stem cells
EPCs
PDGF-BB
Figure 1 POCs are precursors of bone-degrading osteoclasts. Xie et al.4 have now shown that POCs secrete the growth factor PDGF-BB, leading to increased migration and proliferation of mesenchymal stem cells, which give rise to osteoprogenitor cells and subsequently bone-forming osteoblasts. POCderived PDGF-BB is also crucial for the formation of CD31hiEmcnhi (type H) blood vessels in the bone, which have previously been shown to promote osteogenesis in a paracrine fashion. EPCs may also be a target of PDGF-BB, but the precise nature of these cells and their role in the bone vasculature remain undefined. CTSK inhibition, which has been proposed as an antiosteoporosis treatment, compromises osteoclast function and leads to the accumulation of POCs. Xie et al.4 showed that the increase in bone mass in normal and osteoporotic mice by inhibition of CTSK is dependent on POC/osteoclast-derived PDGF-BB.
bone thickness and bone formation were strongly decreased in POC/osteoclast-specific Pdgfb mutants relative to control littermates. The authors also observed that Pdgfb-mutant long bone had a profound reduction of bone vasculature, including fewer CD31hiEmcnhi endothelial cells (Fig. 1). Recent work has shown that these represent a small fraction of the total bone endothelium but are distinct from other endothelial cells because of their ability to support osteoprogenitors2,3. Together, the findings suggest that PDGF-BB produced by POCs contributes to both bone formation and vascularization in mice. How does POC-derived PDGF-BB mediate these effects on bone? PDGF-BB is known to regulate MSCs8, which are essential for osteoblast formation and thereby osteogenesis (Fig. 1). Furthermore, MSCs are also a source of vascular endothelial growth factor (VEGF), a master regulator of angiogenesis in many tissues9. Therefore, it seems likely that at least part of the beneficial effects of POC-derived PDGF-BB on bone formation and vascularization are mediated by actions on MSCs. The authors also found that PDGF-BB induced migration of bone marrow–derived endothelial progenitor cells (EPCs) in vitro (Fig. 1). However it should be noted that the term EPC has been used in the literature to describe a variety of very different bone marrow–derived cell populations, including certain monocytes and a subpopulation of cells that have the potential to differentiate
into endothelial cells but make very minor contributions to angiogenesis10. Given this, a more detailed characterization of the EPCs studied by Xie et al.4 and further evidence that these cells can be incorporated into the bone vasculature is a priority for future research. In addition, it has not yet been shown directly that differentiation of EPCs in response to PDGF-BB can drive the growth of bone endothelium. Indeed, EPCs could contribute to bone angiogenesis indirectly through the paracrine release of VEGF or other growth factors, and this possibility also warrants further investigation. Because both angiogenesis and osteoblast migration are positively regulated by sphingosine-1-phosphate (S1P), the product of sphingosine kinase 1 (Sphk1)-mediated phosphorylation of sphingosine11,12, Xie et al.4 measured levels of S1P secretion and Sphk1 expression in cultured POCs or osteoclasts. Both were significantly reduced in POCs lacking Pdgfb. This suggests a possible signaling pathway through which PDGF-BB mediates its effects on bone formation and vascularization. Taken together, it remains unclear whether PDGF-BB promotes vessel growth through the proliferation or recruitment of PDGFR-β–positive mesenchymal cells, by regulating release of VEGF, or via other mechanisms such as the regulation of S1P and Sphk1. Xie et al.4 also show that PDGF-BB secretion by POCs has implications for the treatment of bone disease, such as osteoporosis,
nature medicine volume 20 | number 11 | november 2014
which is associated with a progressive loss of bone mass and density. A recently identified target for osteoporosis treatment is cathepsin K (CTSK), a cysteine protease, which regulates bone degradation. Knockout of the Ctsk gene in mice causes osteopetrosis, a pathological increase in bone density, due to impaired bone-resorbing activity of POCs and osteoclasts13, and CTSK inhibitors are in clinical trials for the treatment of postmenopausal osteoporosis. Xie et al.4 have now shown that PDGF-BB is required for the effects of CTSK inhibition on bone mass. POCs derived from Ctsk-deficient mice or CTSK inhibitor–treated wild-type mice had increased levels of PDGF-BB and S1P production. PDGF-BB and VEGF levels were also elevated in inhibitor-treated mice or Ctsk-deficient mice, which showed increased vascularization, greater abundance of CD31hiEmcnhi vessels and enhanced bone formation. Strikingly, the beneficial effects of CTSK inhibition on bone vascularization and osteogenesis were lost after POC/osteoclastspecific inactivation of the Pdgfb gene. Thus, PDGF-BB secretion by cells of the osteoclast lineage is essential for the efficacy of a putative antiosteoporotic treatment. As the incidence of osteoporosis is highest in postmenopausal women, ovariectomized mice are frequently used to model this condition. Xie et al.4 found that reduced bone formation in these mice was accompanied by a drop in PDGF-BB concentration in the bone marrow and blood, lower VEGF levels, a reduction in PDGF-BB–expressing osteoclast cell number and a decrease in total bone vasculature as well as in CD31hiEmcnhi endothelium. Remarkably, local injection of PDGF-BB into the bone marrow cavity or systemic delivery of a CTSK inhibitor led to increased bone vascularization and greater abundance of CD31hiEmcnhi capillaries in this model. Both experimental strategies significantly improved homeostatic bone formation and thereby increased the thickness of the outermost (cortical) bone layer and the inner volume occupied by spongy (trabecular) bone. This suggests that modulation of PDGF-BB warrants further investigation in the context of osteoporosis, particularly post menopause. Although bone formation and degradation have traditionally been seen as independent processes, increasing evidence suggests that they are coupled through the crosstalk of different cell types. The present study has shown that POCs, which give rise to boneresorbing osteoclasts, also produce signals such as PDGF-BB and S1P that can boost the function of the osteoblast lineage or angiogenesis, respectively. Similarly, blood vessels, 1239
news and views different cell types in the bone is important for understanding skeletal homeostasis in healthy subjects and may facilitate development of treatments for osteoporosis and other diseases of bone formation and repair. COMPETING FINANCIAL INTERESTS The authors declare no competing financial interests. 1. Maes, C. et al. Dev. Cell 19, 329–344 (2010). 2. Kusumbe, A.P., Ramasamy, S.K. & Adams, R.H. Nature 507, 323–328 (2014). 3. Ramasamy, S.K., Kusumbe, A.P., Wang, L. & Adams, R.H. Nature 507, 376–380 (2014).
4. Xie, H. et al. Nat. Med. 20, 1270–1278 (2014). 5. Kreja, L. et al. J. Cell. Biochem. 109, 347–355 (2010). 6. Sanchez-Fernandez, M.A. et al. PLoS ONE 3, e3537 (2008). 7. Andrae, J., Gallini, R. & Betsholtz, C. Genes Dev. 22, 1276–1312 (2008). 8. Ball, S.G., Shuttleworth, C.A. & Kielty, C.M. J. Cell. Mol. Med. 11, 1012–1030 (2007). 9. Olsson, A.K. Dimberg, A., Kreuger, J. & Claesson-Welsh, L. Nat. Rev. Mol. Cell Biol. 7, 359–371 (2006). 10. Richardson, M.R. & Yoder, M.C. 50, 266–272 (2011). 11. Mendelson, K., Evans, T. & Hla, T. Development 141, 5–9 (2014). 12. Ryu, J. et al. EMBO J. 25, 5840–5851 (2006). 13. Saftig, P. et al. Proc. Natl. Acad. Sci. USA 95, 13453–13458 (1998).
npg
© 2014 Nature America, Inc. All rights reserved.
and in particular the CD31hiEmcnhi subset, support osteoprogenitors and enhance bone formation2,3. It is also likely that the vascular conduit system is crucial for the recruitment of osteoclasts and their progenitors. These examples suggest that blood vessels, osteoblasts, osteoclasts and their respective progenitors are functionally linked. The study by Xie et al.4 has opened up new directions in osteoporosis research that may have important therapeutic implications. Unraveling the communication between
1240
volume 20 | number 11 | november 2014 nature medicine
npg
© 2014 Nature America, Inc. All rights reserved.
inhibition of AEP could have multiple benefits, by reducing cleavage of tau and decreasing tau phosphorylation in part by the reduced processing of PP2AI10. However, potential AEP inhibitors would need a high substrate specificity for tau and PPA2I for therapeutic applications in order to avoid undesired side effects. Another important consideration is whether an AEP targeting strategy would be suitable only in patients with high AEP activity or for more general use in AD10. It will also be important to explore whether such therapy would be more effective for preventive purposes in healthy or presymptomatic individuals. As AEP levels are increased in aging mice, aged individuals may be good candidates for this treatment approach to prevent tau dysfunction.
This study provides evidence for the direct cleavage of tau by AEP and suggests links between different pathogenic hallmarks in AD, including the enhancement of AEP cleavage of tau by amyloid-β and facilitation of tau phosphorylation through its truncation by AEP. The central role of AEP activity in tau pathology makes this enzyme an attractive therapeutic target for AD and other neurodegenerative disorders associated with neurofibrillary tangles. COMPETING FINANCIAL INTERESTS The author declares no competing financial interests. 1. Arriagada, P.V., Growdon, J.H., Hedley-Whyte, E.T. & Hyman, B.T. Neurology 42, 631–639 (1992). 2. Ballatore, C., Lee, V.M. & Trojanowski, J.Q. Nat. Rev. Neurosci. 8, 663–672 (2007).
3. Avila, J., Lucas, J.J., Perez, M. & Hernandez, F. Physiol. Rev. 84, 361–384 (2004). 4. Mandelkow, E.M. & Mandelkow, E. Cold Spring Harb. Perspect. Med. 2, a006247 (2012). 5. Binder, L.I., Guillozet-Bongaarts, A.L., Garcia-Sierra, F. & Berry, R.W. Biochim. Biophys. Acta 1739, 216–223 (2005). 6. Wang, Y., Garg, S., Mandelkow, E.M. & Mandelkow, E. Biochem. Soc. Trans. 38, 955–961 (2010). 7. Zhang, Z. et al. Nat. Med. 20, 1254–1262 (2014). 8. Liu, Z. et al. Mol. Cell 29, 665–678 (2008). 9. Herskowitz, J.H. et al. Proteomics 12, 2455–2463 (2012). 10. Basurto-Islas, G., Grundke-Iqbal, I., Tung, Y.C., Liu, F. & Iqbal, K. J. Biol. Chem. 288, 17495–17507 (2013). 11. Rapoport, M., Dawson, H.N., Binder, L.I., Vitek, M.P. & Ferreira, A. Proc. Natl. Acad. Sci. USA 99, 6364–6369 (2002). 12. Park, S.Y. & Ferreira, A. J. Neurosci. 25, 5365–5375 (2005). 13. Kayed, R. et al. Science 300, 486–489 (2003). 14. Clavaguera, F. et al. Brain Pathol. 23, 342–349 (2013). 15. Nakamura, Y. et al. Neurosci. Lett. 130, 195–198 (1991).
Osteoclast progenitors promote bone vascularization and osteogenesis Anjali P Kusumbe & Ralf H Adams Preosteoclasts give rise to bone-resorbing osteoclasts, which are crucial for skeletal homeostasis. A study now shows that preosteoclasts also contribute to bone formation by releasing platelet-derived growth factor-BB, which promotes bone vascularization and osteogenesis. The skeleton is a dynamic tissue, and its lifelong maintenance relies on the balance of two ongoing processes. Bone is resorbed by osteoclasts, which are phagocytic cells generated by the fusion of monocytes, and new bone is generated by osteoblasts. Osteoblasts are derived from osteoprogenitors, which, in turn, are formed by self-renewing mesenchymal stem cells (MSCs). During bone fracture repair, osteoprogenitors invade the lesioned area together with growing blood vessels1. Increasing evidence indicates that blood vessel growth not only establishes local circulation in the newly formed bone, and thereby access to nutrients and oxygen, but also directly promotes bone formation1–3. In particular, a subset of capillaries expressing high levels of the markers CD31 and endomucin (termed CD31hiEmcnhi or type H) has recently been shown to drive postnatal angiogenesis in the skeletal system and promote Anjali P. Kusumbe and Ralf H. Adams are at the Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, and in the Faculty of Medicine, University of Münster, Münster, Germany. e-mail: [email protected]
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osteogenesis through the release of secreted factors2,3. However, the molecular cross talk between different cell populations in the skeletal system is not fully understood. In this issue of Nature Medicine, Xie et al.4 now show that preosteoclasts (POCs), the immature progenitors of bone-degrading osteoclasts, enhance angiogenesis and osteogenesis during bone remodeling through the release of platelet-derived growth factor-B. The authors of the study refer to it as PDGF-BB, the homodimeric form of the growth factor. They began by investigating the role of osteoclast-lineage cells in periosteal bone formation using mice lacking the gene encoding cytokine colony stimulating factor-1 (Csf), which is essential for the survival of cells in the monocyte/ macrophage lineage. This leads to the absence of osteoclasts and their progenitors. The authors found that Csf1−/− mice had thin cortical bones and decreased bone vascularization. To investigate whether these defects were caused by a loss of signals secreted by POCs or osteoclasts, the authors collected supernatants from these cells in culture and analyzed their effect on MSC migration. Supernatant from POCs increased MSC migration,
whereas supernatant from osteoclasts had no effect. Using a systematic approach involving neutralizing antibodies targeting various candidate molecules, the authors identified PDGF-BB, but not the related growth factor homodimer PDGF-AA, as a POC-secreted factor contributing to MSC migration. This supported previous findings that PDGF-BB is released by immature and nonresorbing osteoclasts5,6. PDGF-BB is mitogenic and chemotactic and promotes the proliferation and migration of many different mesenchymal cell types such as MSCs, pericytes and fibroblasts7. These cell types express the PDGF-BB receptor PDGFR-β, which can trigger a range of signal transduction processes including the mitogenactivated kinase and phosphoinositide3 kinase–Akt cascades. Mice lacking the Pdgfb gene in all cells die shortly after birth due to hemorrhaging and kidney defects. Xie et al.4 have now used the Cre-loxP approach to inactivate Pdgfb specifically in osteoclastlineage cells. This confirmed that the osteoclast lineage is a major source of PDGF-BB in peripheral blood and bone marrow. Moreover, trabecular bone mass, cortical
volume 20 | number 11 | november 2014 nature medicine
news and views
Bone degradation
Osteoprogenitors Bone formation
Osteoclasts
npg
© 2014 Nature America, Inc. All rights reserved.
Katie Vicari/Nature Publishing Group
Bone vascularization CTSK inhibitor
Osteoblasts ?
Differentiation ↑Migration ↑Proliferation
Accumulation of POCs
POCs
↑Migration ↑Proliferation
Mesenchymal Type H ECs stem cells
EPCs
PDGF-BB
Figure 1 POCs are precursors of bone-degrading osteoclasts. Xie et al.4 have now shown that POCs secrete the growth factor PDGF-BB, leading to increased migration and proliferation of mesenchymal stem cells, which give rise to osteoprogenitor cells and subsequently bone-forming osteoblasts. POCderived PDGF-BB is also crucial for the formation of CD31hiEmcnhi (type H) blood vessels in the bone, which have previously been shown to promote osteogenesis in a paracrine fashion. EPCs may also be a target of PDGF-BB, but the precise nature of these cells and their role in the bone vasculature remain undefined. CTSK inhibition, which has been proposed as an antiosteoporosis treatment, compromises osteoclast function and leads to the accumulation of POCs. Xie et al.4 showed that the increase in bone mass in normal and osteoporotic mice by inhibition of CTSK is dependent on POC/osteoclast-derived PDGF-BB.
bone thickness and bone formation were strongly decreased in POC/osteoclast-specific Pdgfb mutants relative to control littermates. The authors also observed that Pdgfb-mutant long bone had a profound reduction of bone vasculature, including fewer CD31hiEmcnhi endothelial cells (Fig. 1). Recent work has shown that these represent a small fraction of the total bone endothelium but are distinct from other endothelial cells because of their ability to support osteoprogenitors2,3. Together, the findings suggest that PDGF-BB produced by POCs contributes to both bone formation and vascularization in mice. How does POC-derived PDGF-BB mediate these effects on bone? PDGF-BB is known to regulate MSCs8, which are essential for osteoblast formation and thereby osteogenesis (Fig. 1). Furthermore, MSCs are also a source of vascular endothelial growth factor (VEGF), a master regulator of angiogenesis in many tissues9. Therefore, it seems likely that at least part of the beneficial effects of POC-derived PDGF-BB on bone formation and vascularization are mediated by actions on MSCs. The authors also found that PDGF-BB induced migration of bone marrow–derived endothelial progenitor cells (EPCs) in vitro (Fig. 1). However it should be noted that the term EPC has been used in the literature to describe a variety of very different bone marrow–derived cell populations, including certain monocytes and a subpopulation of cells that have the potential to differentiate
into endothelial cells but make very minor contributions to angiogenesis10. Given this, a more detailed characterization of the EPCs studied by Xie et al.4 and further evidence that these cells can be incorporated into the bone vasculature is a priority for future research. In addition, it has not yet been shown directly that differentiation of EPCs in response to PDGF-BB can drive the growth of bone endothelium. Indeed, EPCs could contribute to bone angiogenesis indirectly through the paracrine release of VEGF or other growth factors, and this possibility also warrants further investigation. Because both angiogenesis and osteoblast migration are positively regulated by sphingosine-1-phosphate (S1P), the product of sphingosine kinase 1 (Sphk1)-mediated phosphorylation of sphingosine11,12, Xie et al.4 measured levels of S1P secretion and Sphk1 expression in cultured POCs or osteoclasts. Both were significantly reduced in POCs lacking Pdgfb. This suggests a possible signaling pathway through which PDGF-BB mediates its effects on bone formation and vascularization. Taken together, it remains unclear whether PDGF-BB promotes vessel growth through the proliferation or recruitment of PDGFR-β–positive mesenchymal cells, by regulating release of VEGF, or via other mechanisms such as the regulation of S1P and Sphk1. Xie et al.4 also show that PDGF-BB secretion by POCs has implications for the treatment of bone disease, such as osteoporosis,
nature medicine volume 20 | number 11 | november 2014
which is associated with a progressive loss of bone mass and density. A recently identified target for osteoporosis treatment is cathepsin K (CTSK), a cysteine protease, which regulates bone degradation. Knockout of the Ctsk gene in mice causes osteopetrosis, a pathological increase in bone density, due to impaired bone-resorbing activity of POCs and osteoclasts13, and CTSK inhibitors are in clinical trials for the treatment of postmenopausal osteoporosis. Xie et al.4 have now shown that PDGF-BB is required for the effects of CTSK inhibition on bone mass. POCs derived from Ctsk-deficient mice or CTSK inhibitor–treated wild-type mice had increased levels of PDGF-BB and S1P production. PDGF-BB and VEGF levels were also elevated in inhibitor-treated mice or Ctsk-deficient mice, which showed increased vascularization, greater abundance of CD31hiEmcnhi vessels and enhanced bone formation. Strikingly, the beneficial effects of CTSK inhibition on bone vascularization and osteogenesis were lost after POC/osteoclastspecific inactivation of the Pdgfb gene. Thus, PDGF-BB secretion by cells of the osteoclast lineage is essential for the efficacy of a putative antiosteoporotic treatment. As the incidence of osteoporosis is highest in postmenopausal women, ovariectomized mice are frequently used to model this condition. Xie et al.4 found that reduced bone formation in these mice was accompanied by a drop in PDGF-BB concentration in the bone marrow and blood, lower VEGF levels, a reduction in PDGF-BB–expressing osteoclast cell number and a decrease in total bone vasculature as well as in CD31hiEmcnhi endothelium. Remarkably, local injection of PDGF-BB into the bone marrow cavity or systemic delivery of a CTSK inhibitor led to increased bone vascularization and greater abundance of CD31hiEmcnhi capillaries in this model. Both experimental strategies significantly improved homeostatic bone formation and thereby increased the thickness of the outermost (cortical) bone layer and the inner volume occupied by spongy (trabecular) bone. This suggests that modulation of PDGF-BB warrants further investigation in the context of osteoporosis, particularly post menopause. Although bone formation and degradation have traditionally been seen as independent processes, increasing evidence suggests that they are coupled through the crosstalk of different cell types. The present study has shown that POCs, which give rise to boneresorbing osteoclasts, also produce signals such as PDGF-BB and S1P that can boost the function of the osteoblast lineage or angiogenesis, respectively. Similarly, blood vessels, 1239
news and views different cell types in the bone is important for understanding skeletal homeostasis in healthy subjects and may facilitate development of treatments for osteoporosis and other diseases of bone formation and repair. COMPETING FINANCIAL INTERESTS The authors declare no competing financial interests. 1. Maes, C. et al. Dev. Cell 19, 329–344 (2010). 2. Kusumbe, A.P., Ramasamy, S.K. & Adams, R.H. Nature 507, 323–328 (2014). 3. Ramasamy, S.K., Kusumbe, A.P., Wang, L. & Adams, R.H. Nature 507, 376–380 (2014).
4. Xie, H. et al. Nat. Med. 20, 1270–1278 (2014). 5. Kreja, L. et al. J. Cell. Biochem. 109, 347–355 (2010). 6. Sanchez-Fernandez, M.A. et al. PLoS ONE 3, e3537 (2008). 7. Andrae, J., Gallini, R. & Betsholtz, C. Genes Dev. 22, 1276–1312 (2008). 8. Ball, S.G., Shuttleworth, C.A. & Kielty, C.M. J. Cell. Mol. Med. 11, 1012–1030 (2007). 9. Olsson, A.K. Dimberg, A., Kreuger, J. & Claesson-Welsh, L. Nat. Rev. Mol. Cell Biol. 7, 359–371 (2006). 10. Richardson, M.R. & Yoder, M.C. 50, 266–272 (2011). 11. Mendelson, K., Evans, T. & Hla, T. Development 141, 5–9 (2014). 12. Ryu, J. et al. EMBO J. 25, 5840–5851 (2006). 13. Saftig, P. et al. Proc. Natl. Acad. Sci. USA 95, 13453–13458 (1998).
npg
© 2014 Nature America, Inc. All rights reserved.
and in particular the CD31hiEmcnhi subset, support osteoprogenitors and enhance bone formation2,3. It is also likely that the vascular conduit system is crucial for the recruitment of osteoclasts and their progenitors. These examples suggest that blood vessels, osteoblasts, osteoclasts and their respective progenitors are functionally linked. The study by Xie et al.4 has opened up new directions in osteoporosis research that may have important therapeutic implications. Unraveling the communication between
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volume 20 | number 11 | november 2014 nature medicine
