Signaling Pathways Affecting Skeletal Health - Current Osteoporosis Reports
- ️Marie, Pierre J.
- ️Tue Jun 19 2012
Jilka RL. Molecular and cellular mechanisms of the anabolic effect of intermittent PTH. Bone. 2007;40:1434–46.
Bellido T, Ali AA, Gubrij I, Plotkin LI, Fu Q, O’Brien CA, et al. Chronic elevation of parathyroid hormone in mice reduces expression of sclerostin by osteocytes: a novel mechanism for hormonal control of osteoblastogenesis. Endocrinology. 2005;146:4577–83.
Keller H, Kneissel M. SOST is a target gene for PTH in bone. Bone. 2005;37:148–58.
Robling AG, Kedlaya R, Ellis SN, Childress PJ, Bidwell JP, Bellido T, et al. Anabolic and catabolic regimens of human parathyroid hormone 1-34 elicit bone- and envelope-specific attenuation of skeletal effects in Sost-deficient mice. Endocrinology. 2011;152:2963–75.
Rhee Y, Allen MR, Condon K, Lezcano V, Ronda AC, Galli C, et al. PTH receptor signaling in osteocytes governs periosteal bone formation and intracortical remodeling. J Bone Miner Res. 2011;26:1035–46.
Guo J, Liu M, Yang D, Bouxsein ML, Saito H, Galvin RJ, et al. Suppression of Wnt signaling by Dkk1 attenuates PTH-mediated stromal cell response and new bone formation. Cell Metab. 2010;11:161–71.
Bedi B, Li JY, Tawfeek H, Baek KH, Adams J, Vangara SS, et al. Silencing of parathyroid hormone (PTH) receptor 1 in T cells blunts the bone anabolic activity of PTH. Proc Natl Acad Sci U S A. 2012;109:E725–33.
Wan M, Yang C, Li J, Wu X, Yuan H, Ma H, et al. Parathyroid hormone signaling through low-density lipoprotein-related protein 6. Genes Dev. 2008;22:2968–79.
Taurin S, Sandbo N, Qin Y, Browning D, Dulin NO. Phosphorylation of beta-catenin by cyclic AMP-dependent protein kinase. J Biol Chem. 2006;281:9971–6.
Wu JY, Aarnisalo P, Bastepe M, Sinha P, Fulzele K, Selig MK, et al. Gsalpha enhances commitment of mesenchymal progenitors to the osteoblast lineage but restrains osteoblast differentiation in mice. J Clin Invest. 2011;121:3492–504.
Jilka RL, Almeida M, Ambrogini E, Han L, Roberson PK, Weinstein RS, et al. Decreased oxidative stress and greater bone anabolism in the aged, when compared to the young, murine skeleton with parathyroid hormone administration. Aging Cell. 2010;9:851–67.
Fei Y, Hurley MM. Role of fibroblast growth factor 2 and Wnt signaling in anabolic effects of parathyroid hormone on bone formation. J Cell Physiol. 2012. doi:10.1002/jcp.24075.
Krishnan V, Bryant HU, Macdougald OA. Regulation of bone mass by Wnt signaling. J Clin Invest. 2006;116:1202–9.
• Yadav VK, Ryu JH, Suda N, Tanaka KF, Gingrich JA, Schutz G, et al. Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell. 2008;135:825–37. Reports a novel mechanism by which bone formation is controlled by Lrp5-mediated serotonin production in the duodenum..
Ducy P, Karsenty G. The two faces of serotonin in bone biology. J Cell Biol. 2010;191:7–13.
Yadav VK, Balaji S, Suresh PS, Liu XS, Lu X, Li Z, et al. Pharmacological inhibition of gut-derived serotonin synthesis is a potential bone anabolic treatment for osteoporosis. Nat Med. 2010;16:308–12.
Inose H, Zhou B, Yadav VK, Guo XE, Karsenty G, Ducy P. Efficacy of serotonin inhibition in mouse models of bone loss. J Bone Miner Res. 2011;26:2002–11.
• Cui Y, Niziolek PJ, MacDonald BT, Zylstra CR, Alenina N, Robinson DR, et al. Lrp5 functions in bone to regulate bone mass. Nat Med. 2011;17:684–91. Reports a number of genetic studies supporting a functional role of Lrp5 in bone to control bone mass..
Goltzman D. LRP5, serotonin, and bone: complexity, contradictions, and conundrums. J Bone Miner Res. 2011;26:1997–2001.
Collet C, Schiltz C, Geoffroy V, Maroteaux L, Launay JM, de Vernejoul MC. The serotonin 5-HT2B receptor controls bone mass via osteoblast recruitment and proliferation. FASEB J. 2008;22:418–27.
Chabbi-Achengli Y, Coudert AE, Callebert J, Geoffroy V, Cote F, Collet C, et al. Decreased osteoclastogenesis in serotonin-deficient mice. Proc Natl Acad Sci U S A. 2012;109:2567–72.
Stevens JR, Miranda-Carboni GA, Singer MA, Brugger SM, Lyons KM, Lane TF. Wnt10b deficiency results in age-dependent loss of bone mass and progressive reduction of mesenchymal progenitor cells. J Bone Miner Res. 2010;25:2138–47.
Cawthorn WP, Bree AJ, Yao Y, Du B, Hemati N, Martinez-Santibanez G, et al. Wnt6, Wnt10a and Wnt10b inhibit adipogenesis and stimulate osteoblastogenesis through a beta-catenin-dependent mechanism. Bone. 2012;50:477–89.
Robling AG, Turner CH. Mechanical signaling for bone modeling and remodeling. Crit Rev Eukaryot Gene Expr. 2009;19:319–38.
• Tu X, Rhee Y, Condon KW, Bivi N, Allen MR, Dwyer D, et al. Sost downregulation and local Wnt signaling are required for the osteogenic response to mechanical loading. Bone. 2012;50:209–17. Reports the essential roles of the Wnt inhibitor Sost and Wnt signaling in the anabolic effect of mechanical forces on bone..
Marsell R, Sisask G, Nilsson Y, Sundgren-Andersson AK, Andersson U, Larsson S, et al. GSK-3 inhibition by an orally active small molecule increases bone mass in rats. Bone. 2012;50:619–27.
Berendsen AD, Fisher LW, Kilts TM, Owens RT, Robey PG, Gutkind JS, et al. Modulation of canonical Wnt signaling by the extracellular matrix component biglycan. Proc Natl Acad Sci U S A. 2011;108:17022–7.
Glantschnig H, Scott K, Hampton R, Wei N, McCracken P, Nantermet P, et al. A rate-limiting role for Dickkopf-1 in bone formation and the remediation of bone loss in mouse and primate models of postmenopausal osteoporosis by an experimental therapeutic antibody. J Pharmacol Exp Ther. 2011;338:568–78.
• Li X, Ominsky MS, Warmington KS, Morony S, Gong J, Cao J, et al. Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. J Bone Miner Res. 2009;24:578–88. Reports the positive effects of pharmacological inhibition of sclerostin on bone formation and bone mass in osteopenic rats..
Padhi D, Jang G, Stouch B, Fang L, Posvar E. Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody. J Bone Miner Res. 2011;26(1):19–26.
Lowery JW, Pazin D, Intini G, Kokabu S, Chappuis V, Capelo LP, et al. The role of BMP2 signaling in the skeleton. Crit Rev Eukaryot Gene Expr. 2011;21:177–85.
Mishina Y, Starbuck MW, Gentile MA, Fukuda T, Kasparcova V, Seedor JG, et al. Bone morphogenetic protein type IA receptor signaling regulates postnatal osteoblast function and bone remodeling. J Biol Chem. 2004;279:27560–6.
Kamiya N, Kobayashi T, Mochida Y, Yu PB, Yamauchi M, Kronenberg HM, et al. Wnt inhibitors Dkk1 and Sost are downstream targets of BMP signaling through the type IA receptor (BMPRIA) in osteoblasts. J Bone Miner Res. 2010;25:200–10.
Okamoto M, Murai J, Imai Y, Ikegami D, Kamiya N, Kato S, et al. Conditional deletion of Bmpr1a in differentiated osteoclasts increases osteoblastic bone formation, increasing volume of remodeling bone in mice. J Bone Miner Res. 2011;26:2511–22.
Gazzerro E, Canalis E. Bone morphogenetic proteins and their antagonists. Rev Endocr Metab Disord. 2006;7:51–65.
Ono M, Inkson CA, Kilts TM, Young MF. WISP-1/CCN4 regulates osteogenesis by enhancing BMP-2 activity. J Bone Miner Res. 2011;26:193–208.
Janssens K, ten Dijke P, Janssens S, Van Hul W. Transforming growth factor-beta1 to the bone. Endocr Rev. 2005;26:743–74.
Edwards JR, Nyman JS, Lwin ST, Moore MM, Esparza J, O’Quinn EC, et al. Inhibition of TGF-beta signaling by 1D11 antibody treatment increases bone mass and quality in vivo. J Bone Miner Res. 2010;25:2419–26.
Nicks KM, Perrien DS, Akel NS, Suva LJ, Gaddy D. Regulation of osteoblastogenesis and osteoclastogenesis by the other reproductive hormones, Activin and Inhibin. Mol Cell Endocrinol. 2009;310:11–20.
Eijken M, Swagemakers S, Koedam M, Steenbergen C, Derkx P, Uitterlinden AG, et al. The activin A-follistatin system: potent regulator of human extracellular matrix mineralization. FASEB J. 2007;21:2949–60.
• Lotinun S, Pearsall RS, Davies MV, Marvell TH, Monnell TE, Ucran J, et al. A soluble activin receptor Type IIA fusion protein (ACE-011) increases bone mass via a dual anabolic-antiresorptive effect in Cynomolgus monkeys. Bone. 2010;46:1082–8. Reports that am ActRIIA soluble receptor that prevents signaling through the endogenous activin receptor decreases bone resorption and increases bone formation, leading to enhanced mechanical strength and bone quality..
Lotinun S, Pearsall RS, Horne WC, Baron R. Activin receptor signaling: a potential therapeutic target for osteoporosis. Curr Mol Pharmacol. 2012.
Schneider MR, Sibilia M, Erben RG. The EGFR network in bone biology and pathology. Trends Endocrinol Metab. 2009;20:517–24.
Zhang X, Tamasi J, Lu X, Zhu J, Chen H, Tian X, et al. Epidermal growth factor receptor plays an anabolic role in bone metabolism in vivo. J Bone Miner Res. 2011;26:1022–34.
Schneider MR, Mayer-Roenne B, Dahlhoff M, Proell V, Weber K, Wolf E, et al. High cortical bone mass phenotype in betacellulin transgenic mice is EGFR dependent. J Bone Miner Res. 2009;24:455–67.
Schneider MR, Dahlhoff M, Andrukhova O, Grill J, Glosmann M, Schuler C, et al. Normal epidermal growth factor receptor signaling is dispensable for bone anabolic effects of parathyroid hormone. Bone. 2012;50:237–44.
Marie PJ, Miraoui H, Severe N. FGF/FGFR signaling in bone formation: progress and perspectives. Growth Factors. 2012;30(2):117–23.
Miraoui H, Oudina K, Petite H, Tanimoto Y, Moriyama K, Marie PJ. Fibroblast growth factor receptor 2 promotes osteogenic differentiation in mesenchymal cells via ERK1/2 and protein kinase C signaling. J Biol Chem. 2009;284:4897–904.
Fei Y, Xiao L, Doetschman T, Coffin DJ, Hurley MM. Fibroblast growth factor 2 stimulation of osteoblast differentiation and bone formation is mediated by modulation of the wnt signaling pathway. J Biol Chem. 2011;286:40575–83.
Govoni KE. Insulin-like growth factor-I molecular pathways in osteoblasts: potential targets for pharmacological manipulation. Curr Mol Pharmacol. 2012.
Zhang M, Xuan S, Bouxsein ML, von Stechow D, Akeno N, Faugere MC, et al. Osteoblast-specific knockout of the insulin-like growth factor (IGF) receptor gene reveals an essential role of IGF signaling in bone matrix mineralization. J Biol Chem. 2002;277:44005–12.
Zhao G, Monier-Faugere MC, Langub MC, Geng Z, Nakayama T, Pike JW, et al. Targeted overexpression of insulin-like growth factor I to osteoblasts of transgenic mice: increased trabecular bone volume without increased osteoblast proliferation. Endocrinology. 2000;141:2674–82.
Yakar S, Canalis E, Sun H, Mejia W, Kawashima Y, Nasser P, et al. Serum IGF-1 determines skeletal strength by regulating subperiosteal expansion and trait interactions. J Bone Miner Res. 2009;24:1481–92.
Kesavan C, Wergedal JE, Lau KH, Mohan S. Conditional disruption of IGF-I gene in type 1alpha collagen-expressing cells shows an essential role of IGF-I in skeletal anabolic response to loading. Am J Physiol Endocrinol Metab. 2011;301:E1191–7.
Kawai M, Breggia AC, DeMambro VE, Shen X, Canalis E, Bouxsein ML, et al. The heparin-binding domain of IGFBP-2 has insulin-like growth factor binding-independent biologic activity in the growing skeleton. J Biol Chem. 2011;286:14670–80.
Miraoui H, Ringe J, Haupl T, Marie PJ. Increased EGF- and PDGF{alpha}-receptor signaling by mutant FGF-receptor 2 contributes to osteoblast dysfunction in Apert craniosynostosis. Hum Mol Genet. 2010;19(9):1678–89.
Miraoui H, Marie PJ. Fibroblast growth factor receptor signaling crosstalk in skeletogenesis. Sci Signal. 2010;3(146):re9.
• Sévère N, Miraoui H, Marie PJ. The Casitas B lineage lymphoma (Cbl) mutant G306E enhances osteogenic differentiation in human mesenchymal stromal cells in part by decreased Cbl-mediated platelet-derived growth factor receptor alpha and fibroblast growth factor receptor 2 ubiquitination. J Biol Chem. 2011;286:24443–50. Reports the first demonstration that inhibition of Cbl interaction with specific receptor tyrosine kinases results in increased osteogenic differentiation of osteoblast progenitor cells..
Brennan T, Adapala NS, Barbe MF, Yingling V, Sanjay A. Abrogation of Cbl-PI3K interaction increases bone formation and osteoblast proliferation. Calcif Tissue Int. 2011;89:396–410.
• Adapala NS, Barbe MF, Langdon WY, Nakamura MC, Tsygankov AY, Sanjay A. The loss of Cbl-phosphatidylinositol 3-kinase interaction perturbs RANKL-mediated signaling, inhibiting bone resorption and promoting osteoclast survival. J Biol Chem. 2011;285:36745–58. Reports that binding of Cbl to PI3K negatively regulates osteoclast differentiation, survival, and signaling events..
Guntur AR, Rosen CJ. The skeleton: a multi-functional complex organ: new insights into osteoblasts and their role in bone formation: the central role of PI3Kinase. J Endocrinol. 2011;211:123–30.
Ling L, Dombrowski C, Foong KM, Haupt LM, Stein GS, Nurcombe V, et al. Synergism between Wnt3a and heparin enhances osteogenesis via a phosphoinositide 3-kinase/Akt/RUNX2 pathway. J Biol Chem. 2010;285:26233–44.
Wu X, Chen S, Orlando SA, Yuan J, Kim ET, Munugalavadla V, et al. p85alpha regulates osteoblast differentiation by cross-talking with the MAPK pathway. J Biol Chem. 2011;286:13512–21.
Liu X, Bruxvoort KJ, Zylstra CR, Liu J, Cichowski R, Faugere MC, et al. Lifelong accumulation of bone in mice lacking Pten in osteoblasts. Proc Natl Acad Sci U S A. 2007;104:2259–64.
Mukherjee A, Rotwein P. Selective signaling by Akt1 controls osteoblast differentiation and osteoblast-mediated osteoclast development. Mol Cell Biol. 2012;32:490–500.
Moon JB, Kim JH, Kim K, Youn BU, Ko A, Lee SY, et al. Akt induces osteoclast differentiation through regulating the GSK3beta/NFATc1 signaling cascade. J Immunol. 2012;188:163–9.
Kang H, Chang W, Hurley M, Vignery A, Wu D. Important roles of PI3Kgamma in osteoclastogenesis and bone homeostasis. Proc Natl Acad Sci U S A. 2010;107:12901–6.
Ge C, Yang Q, Zhao G, Yu H, Kirkwood KL, Franceschi RT. Interactions between extracellular signal-regulated kinase 1/2 and P38 OPG pathways in the control of RUNX2 phosphorylation and transcriptional activity. J Bone Miner Res. 2012;27(3):538–51.
Ortuno MJ, Ruiz-Gaspa S, Rodriguez-Carballo E, Susperregui AR, Bartrons R, Rosa JL, et al. p38 regulates expression of osteoblast-specific genes by phosphorylation of osterix. J Biol Chem. 2010;285:31985–94.
• Greenblatt MB, Shim JH, Zou W, Sitara D, Schweitzer M, Hu D, et al. The p38 MAPK pathway is essential for skeletogenesis and bone homeostasis in mice. J Clin Invest. 2010;120:2457–73. Reports the important role of the MAPK p38β signaling in bone formation in vivo and suggests that selective p38β agonists may prevent bone loss associated with osteoporosis..
Whitehouse CA, Waters S, Marchbank K, Horner A, McGowan NW, Jovanovic JV, et al. Neighbor of Brca1 gene (Nbr1) functions as a negative regulator of postnatal osteoblastic bone formation and p38 MAPK activity. Proc Natl Acad Sci U S A. 2010;107:12913–8.
Chen JR, Lazarenko OP, Wu X, Kang J, Blackburn ML, Shankar K, et al. Dietary-induced serum phenolic acids promote bone growth via p38 MAPK/beta-catenin canonical Wnt signaling. J Bone Miner Res. 2010;25:2399–411.
Caverzasio J, Manen D. Essential role of Wnt3a-mediated activation of mitogen-activated protein kinase p38 for the stimulation of alkaline phosphatase activity and matrix mineralization in C3H10T1/2 mesenchymal cells. Endocrinology. 2007;148:5323–30.
Chang W, Tu C, Chen TH, Bikle D, Shoback D. The extracellular calcium-sensing receptor (CaSR) is a critical modulator of skeletal development. Sci Signal. 2008;1:ra1.
Marie PJ. The calcium-sensing receptor in bone cells: a potential therapeutic target in osteoporosis. Bone. 2010;46:571–6.
•• Dvorak-Ewell MM, Chen TH, Liang N, Garvey C, Liu B, Tu C, et al. Osteoblast extracellular Ca2+-sensing receptor regulates bone development, mineralization, and turnover. J Bone Miner Res. 2011;26:2935–47. Reports the important role of CaR signaling in the regulation of bone remodeling..
Xue Y, Xiao Y, Liu J, Karaplis AC, Pollack MR, Brown EM, et al. The calcium sensing receptor complements parathyroid hormone-induced bone turnover in discrete skeletal compartments in mice. Am J Physiol Endocrinol Metab. 2012;302(7):E841–51.
Marie PJ. Strontium ranelate in osteoporosis and beyond: identifying molecular targets in bone cell biology. Mol Interv. 2010;10:305–12.
Fromigué O, Hay E, Barbara A, Petrel C, Traiffort E, Ruat M, et al. Calcium sensing receptor-dependent and receptor-independent activation of osteoblast replication and survival by strontium ranelate. J Cell Mol Med. 2009;13:2189–99.
Fromigué O, Hay E, Barbara A, Marie PJ. Essential role of nuclear factor of activated T cells (NFAT)-mediated Wnt signaling in osteoblast differentiation induced by strontium ranelate. J Biol Chem. 2010;285:25251–8.
Caudrillier A, Hurtel-Lemaire AS, Wattel A, Cournarie F, Godin C, Petit L, et al. Strontium ranelate decreases RANKL-induced osteoclastic differentiation in vitro: involvement of the calcium sensing receptor. Mol Pharmacol. 2010;78(4):569–76.
Hurtel-Lemaire AS, Mentaverri R, Caudrillier A, Cournarie F, Wattel A, Kamel S, et al. The calcium-sensing receptor is involved in strontium ranelate-induced osteoclast apoptosis. New insights into the associated signaling pathways. J Biol Chem. 2009;284:575–84.
Brennan TC, Rybchyn MS, Green W, Atwa S, Conigrave AD, Mason RS. Osteoblasts play key roles in the mechanisms of action of strontium ranelate. Br J Pharmacol. 2009;157:1291–300.
Peng S, Liu XS, Zhou G, Li Z, Luk KD, Guo XE, et al. Osteoprotegerin deficiency attenuates strontium-mediated inhibition of osteoclastogenesis and bone resorption. J Bone Miner Res. 2011;26(6):1272–82.
Reginster JY, Bruyere O. Collette J. Bone: Strontium ranelate treatment increases osteoprotegerin serum levels in postmenopausal osteoporotic women; 2012;50(5):1201–2.
Marie PJ. Bone cell–matrix protein interactions. Osteoporos Int. 2009;20:1037–42.
• Hamidouche Z, Fromigué O, Ringe J, Haupl T, Vaudin P, Pages JC, et al. Priming integrin alpha5 promotes human mesenchymal stromal cell osteoblast differentiation and osteogenesis. Proc Natl Acad Sci U S A. 2009;106:18587–91. Establishes that the α5 integrin is required for osteoblast differentiation and provides a targeted strategy to promote osteoblastogenesis for bone repair..
Batra N, Burra S, Siller-Jackson AJ, Gu S, Xia X, Weber GF, et al. Mechanical stress-activated integrin alpha5beta1 induces opening of connexin 43 hemichannels. Proc Natl Acad Sci U S A. 2012;109:3359–64.
Olivares-Navarrete R, Raz P, Zhao G, Chen J, Wieland M, Cochran DL, et al. Integrin alpha2beta1 plays a critical role in osteoblast response to micron-scale surface structure and surface energy of titanium substrates. Proc Natl Acad Sci U S A. 2008;105:15767–72.
•• Guan M, Yao W, Liu R, Lam KS, Nolta J, Jia J, et al. Directing mesenchymal stem cells to bone to augment bone formation and increase bone mass. Nat Med. 2012;18:456–62. Reports the interest of using a peptidomimetic ligand (LLP2A) against integrin α4β1 to target mesenchymal cells and increase bone formation and bone mass..
Di Benedetto A, Watkins M, Grimston S, Salazar V, Donsante C, Mbalaviele G, et al. N-cadherin and cadherin 11 modulate postnatal bone growth and osteoblast differentiation by distinct mechanisms. J Cell Sci. 2010;123:2640–8.
Haÿ E, Laplantine E, Geoffroy V, Frain M, Kohler T, Muller R, et al. N-cadherin interacts with axin and LRP5 to negatively regulate Wnt/beta-catenin signaling, osteoblast function, and bone formation. Mol Cell Biol. 2009;29:953–64.
Haÿ E, Nouraud A, Marie PJ. N-cadherin negatively regulates osteoblast proliferation and survival by antagonizing Wnt, ERK and PI3K/Akt signaling. PLoS One. 2009;4:e8284.
Guntur AR, Rosen CJ, Naski MC. N-cadherin adherens junctions mediate osteogenesis through PI3K signaling. Bone. 2012;50:54–62.
Bivi N, Condon KW, Allen MR, Farlow N, Passeri G, Brun LR, et al. Cell autonomous requirement of connexin 43 for osteocyte survival: consequences for endocortical resorption and periosteal bone formation. J Bone Miner Res. 2012;27(2):374–89.
Zhang Y, Paul EM, Sathyendra V, Davison A, Sharkey N, Bronson S, et al.. Enhanced osteoclastic resorption and responsiveness to mechanical load in gap junction deficient bone. PLoS One. 2011;6:e23516.
Matsuo K. Eph and ephrin interactions in bone. Adv Exp Med Biol. 2010;658:95–103.
•• Irie N, Takada Y, Watanabe Y, Matsuzaki Y, Naruse C, Asano M, et al. Bidirectional signaling through ephrinA2-EphA2 enhances osteoclastogenesis and suppresses osteoblastogenesis. J Biol Chem. 2009;284:14637–44. Reports the essential role of ephrinA2-EphA2 bidirectional signaling in the control of osteoclastogenesis and osteoblastogenesis..
•• Maeda K, Kobayashi Y, Udagawa N, Uehara S, Ishihara A, Mizoguchi T, et al. Wnt5a-Ror2 signaling between osteoblast-lineage cells and osteoclast precursors enhances osteoclastogenesis. Nat Med. 2012;18:405–12. Reports the important role of the Wnt5a-Ror2 pathway in osteoclastogenesis..
•• Negishi-Koga T, Shinohara M, Komatsu N, Bito H, Kodama T, Friedel RH, et al. Suppression of bone formation by osteoclastic expression of semaphorin 4D. Nat Med. 2011;17:1473–80. Reports a novel role for Sema4D-Plexin-B1signaling in bone formation and its potential interest as a target to treat bone loss..