Receptor activator of NF-κB ligand (RANKL) and its receptor activator of NF-κB (RANK) play pivotal roles in osteoclast differentiation and function. However, the structural determinants of the RANK that mediate osteoclast formation and function have not been definitively identified. To address this issue, we developed a chimeric receptor approach that permits a structure/function study of the RANK cytoplasmic domain in osteoclasts. Using this approach, we examined the role of six RANK putative tumor necrosis factor receptor-associated factor-binding motifs (PTM) (PTM1, ILLMT-REE286-293; PTM2, PSQPS349-353; PTM3, PFQEP369-373; PTM4, VYVSQTSQE537-545; PTM5, PVQEET559-564; and PTM6, PVQEQG604-609) in osteoclast formation and function. Our data revealed that the RANK cytoplasmic domain possesses three functional motifs (PFQEP369-373, PVQEET559-564, and PVQEQG604-609) capable of mediating osteoclast formation and function. Moreover, we demonstrated that these motifs play distinct roles in activating intracellular signaling. PFQEP369-373 initiates NF-κB, c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p38 signaling pathways and PVQEET559-564 activates NF-κB and p38 pathways in osteoclasts, whereas PVQEQG604-609 is only capable of activating NF-κB pathway. Significantly, the revelation of these functional RANK cytoplasmic motifs has not only laid a foundation for further delineating RANK signaling pathways in osteoclasts, but, more importantly, these RANK motifs themselves represent potential therapeutic targets for bone disorders such as osteoporosis. Receptor activator of NF-κB ligand (RANKL) and its receptor activator of NF-κB (RANK) play pivotal roles in osteoclast differentiation and function. However, the structural determinants of the RANK that mediate osteoclast formation and function have not been definitively identified. To address this issue, we developed a chimeric receptor approach that permits a structure/function study of the RANK cytoplasmic domain in osteoclasts. Using this approach, we examined the role of six RANK putative tumor necrosis factor receptor-associated factor-binding motifs (PTM) (PTM1, ILLMT-REE286-293; PTM2, PSQPS349-353; PTM3, PFQEP369-373; PTM4, VYVSQTSQE537-545; PTM5, PVQEET559-564; and PTM6, PVQEQG604-609) in osteoclast formation and function. Our data revealed that the RANK cytoplasmic domain possesses three functional motifs (PFQEP369-373, PVQEET559-564, and PVQEQG604-609) capable of mediating osteoclast formation and function. Moreover, we demonstrated that these motifs play distinct roles in activating intracellular signaling. PFQEP369-373 initiates NF-κB, c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p38 signaling pathways and PVQEET559-564 activates NF-κB and p38 pathways in osteoclasts, whereas PVQEQG604-609 is only capable of activating NF-κB pathway. Significantly, the revelation of these functional RANK cytoplasmic motifs has not only laid a foundation for further delineating RANK signaling pathways in osteoclasts, but, more importantly, these RANK motifs themselves represent potential therapeutic targets for bone disorders such as osteoporosis. Osteoclasts, the principal bone-resorbing cells, play a pivotal role in skeleton development and maintenance (1Teitelbaum S.L. Science. 2000; 289: 1504-1508Crossref PubMed Scopus (3104) Google Scholar). Osteoclasts are derived from mononuclear precursors of monocyte/macrophage lineage upon stimulation of two key factors: monocyte/macrophage colony-stimulating factor (M-CSF) 1The abbreviations used are: M-CSF, monocyte/macrophage colony-stimulating factor; PTM, putative TRAF-binding motifs; BMM, bone marrow macrophages; OPG, osteoprotegerin; RANK, receptor activator of NF-κB; RANKL, RANK ligand; TNF, tumor necrosis factor; TNFR, TNF receptor; TRAF, TNF receptor-associated factor; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor κB; TRAP, tartrate-resistant acid phosphatase; TBS, Tris-buffered saline. and receptor activator of nuclear factor κB (RANKL, also known as OPG ligand/osteoclast differentiation factor/TNF-related activation-induced cytokine) (1Teitelbaum S.L. Science. 2000; 289: 1504-1508Crossref PubMed Scopus (3104) Google Scholar, 2Suda T. Takahashi N. Udagawa N. Jimi E. Gillespie M.T. Martin T.J. Endocr. Rev. 1999; 20: 345-357Crossref PubMed Google Scholar, 3Boyle W.J. Simonet W.S. Lacey D.L. Nature. 2003; 423: 337-342Crossref PubMed Scopus (4988) Google Scholar). RANKL was identified as a member of the TNF superfamily independently by several groups in the late 1990s (4Lacey D.L. Timms E. Tan H.L. Kelley M.J. Dunstan C.R. Burgess T. Elliott R. Colombero A. Elliott G. Scully S. Hsu H. Sullivan J Hawkins N. Davy E. Capparelli C. Eli A. Qian Y.X. Kaufman S. Sarosi I Shalhoub V. Senaldi G. Guo J. Delaney J. Boyle W.J. Cell. 1998; 93: 165-176Abstract Full Text Full Text PDF PubMed Scopus (4656) Google Scholar, 5Yasuda H. Shima N. Nakagawa N. Yamaguchi K. Kinosaki M. Mochizuki S. Tomoyasu A. Yano K. Goto M. Murakami A. Tsuda E. Morinaga T. Higashio K. Udagawa N. Takahashi N. Suda T. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 3597-3602Crossref PubMed Scopus (3592) Google Scholar, 6Anderson D.M. Maraskovsky E. Billingsley W.L. Dougall W.C. Tometsko M.E. Roux E.R. Teepe M.C. DuBose R.F. Cosman D. Galibert L. Nature. 1997; 390: 175-179Crossref PubMed Scopus (1960) Google Scholar, 7Wong B.R. Rho J. Arron J. Robinson E. Orlinick J. Chao M Kalachikov S. Cayani E. Bartlett F.S. II I Frankel W.N. Lee S.Y. Choi Y. J. Biol. Chem. 1997; 272: 25190-25194Abstract Full Text Full Text PDF PubMed Scopus (918) Google Scholar). RANKL regulates both osteoclast formation and function by binding to its receptor RANK expressed on osteoclast precursors and mature osteoclasts (4Lacey D.L. Timms E. Tan H.L. Kelley M.J. Dunstan C.R. Burgess T. Elliott R. Colombero A. Elliott G. Scully S. Hsu H. Sullivan J Hawkins N. Davy E. Capparelli C. Eli A. Qian Y.X. Kaufman S. Sarosi I Shalhoub V. Senaldi G. Guo J. Delaney J. Boyle W.J. Cell. 1998; 93: 165-176Abstract Full Text Full Text PDF PubMed Scopus (4656) Google Scholar, 8Hsu H. Lacey D.L. Dunstan C.R. Solovyev I. Colombero A. Timms E. Tan H-L. Elliott G. Kelley M.J. Sarosi I. Wang L. Xia X.Z. Elliott R. Chiu L. Black T. Scully S. Capparelli C. Morony S. Shimamoto G. Bass M.B. Boyle W.J. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 3540-3545Crossref PubMed Scopus (1428) Google Scholar, 9Burgess T.L. Qian Y. Kaufman S. Ring B.D. Van G. Capparelli C. Kelley M. Hsu H. Boyle W.J. Dunstan C.R. Hu S. Lacey D.L. J. Cell Biol. 1999; 145: 527-538Crossref PubMed Scopus (613) Google Scholar). The essential role of both RANKL and RANK in the osteoclastogenic process has been well demonstrated by the findings that mice lacking the gene for either protein develop osteopetrosis caused by failure to form osteoclasts (10Kong Y.Y. Yoshida H. Sarosi I. Tan H.L. Timms E. Capparelli C. Morony S. Oliveira d.S.A. Van G. Itie A. Khoo W. Wakeham A. Dunstan C.R. Lacey D.L. Mak T.W. Boyle W.J. Penninger J.M. Nature. 1999; 397: 315-323Crossref PubMed Scopus (2887) Google Scholar, 11Dougall W.C. Glaccum M. Charrier K. K. K. T. E. J. Tometsko M.E. C.R. A. V. S. Cosman D. D. J. 1999; PubMed Scopus Google Scholar, J. Sarosi I. Morony S. Capparelli C. Tan S. Elliott R. Scully S. Van G. Kaufman S. Y. J. Martin L. K. J. Hsu H. Dunstan C.R. Lacey D.L. Boyle W.J. Proc. Natl. Acad. Sci. U. S. A. 2000; PubMed Scopus Google Scholar). RANK was identified as a member of the TNF receptor D.M. Maraskovsky E. Billingsley W.L. Dougall W.C. Tometsko M.E. Roux E.R. Teepe M.C. DuBose R.F. Cosman D. Galibert L. Nature. 1997; 390: 175-179Crossref PubMed Scopus (1960) Google Scholar). of the TNF receptor are by a of and intracellular by such as TNF receptor-associated the motifs in cytoplasmic Rev. Cell Biol. 1999; PubMed Scopus Google Scholar, 1999; PubMed Google Scholar, N. M.J. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). the of the have been to intracellular signaling. of the have been on the signaling H. Lacey D.L. Dunstan C.R. Solovyev I. Colombero A. Timms E. Tan H-L. Elliott G. Kelley M.J. Sarosi I. Wang L. Xia X.Z. Elliott R. Chiu L. Black T. Scully S. Capparelli C. Morony S. Shimamoto G. Bass M.B. Boyle W.J. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 3540-3545Crossref PubMed Scopus (1428) Google Scholar, V. J. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, B.R. R. Lee S.Y. M. Choi J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, Lee Lee J Lee 1999; PubMed Scopus Google Scholar, J. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, L. Tometsko M.E. D.M. Cosman D. Dougall W.C. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google represent the and of intracellular signaling pathways by these have RANK cytoplasmic capable of by in binding H. Lacey D.L. Dunstan C.R. Solovyev I. Colombero A. Timms E. Tan H-L. Elliott G. Kelley M.J. Sarosi I. Wang L. Xia X.Z. Elliott R. Chiu L. Black T. Scully S. Capparelli C. Morony S. Shimamoto G. Bass M.B. Boyle W.J. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 3540-3545Crossref PubMed Scopus (1428) Google Scholar, V. J. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, B.R. R. Lee S.Y. M. Choi J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, Lee Lee J Lee 1999; PubMed Scopus Google Scholar, J. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, L. Tometsko M.E. D.M. Cosman D. Dougall W.C. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google the of these data to osteoclast the we the signaling in osteoclast differentiation and function in by the RANK motifs osteoclast formation and function. To this we developed a chimeric receptor approach that to a structure/function study of RANK cytoplasmic domain in osteoclast differentiation and function. Using this approach, we have identified three functional motifs that osteoclast differentiation and function. we that these mediate osteoclast differentiation and function by the distinct signaling Our has a functional RANK cytoplasmic motifs and a osteoclast formation and function. Moreover, the of these functional RANK motifs has laid for further delineating the signaling pathways in osteoclast formation and function. and from from was from the domain of was from was from The from Cell p38 and of the we a chimeric the domain to the and cytoplasmic of RANK the domain was by from bone marrow and a of The was II the in a the RANK and cytoplasmic was also by from a the and a the The RANK was and to a The and of the chimeric was by of the M. T. K. D. M. A. T. Cell. Biol. 1998; PubMed Scopus Google and the S. T. T. 2000; PubMed Scopus Google The chimeric from was to in as in S. T. T. 2000; PubMed Scopus Google Scholar). was was and and of marrow from of mice mice as R. K. S.L. J. PubMed Scopus Google Scholar). by bone marrow in essential in the of of of for as S. K. A. J. 2000; PubMed Scopus Google Scholar). The for in the of of of and The further in the of and for and of The used for and in in essential in the of of of is and of J. S. S.L. 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PubMed Scopus Google for on of was to the and the on for The of and in of of was to the was a in the To the six putative TRAF-binding motifs the for and for PTM2, and for PTM3, and for PTM4, and for PTM5, and and for PTM6, and The are by in these The by and in the chimeric to that by the The chimeric as for in essential in the of for RANKL for as in The and in and and of in the of for and for on The to from a The in in binding and three The in the three and in for The and was a from was the of a Receptor of and functional motifs in the RANK cytoplasmic domain mediating osteoclast differentiation and we developed a chimeric receptor of domain to the and intracellular of RANK that both and RANK to the of the and that are both by we that the of the chimeric receptor to RANK intracellular signaling pathways for the osteoclast formation function To the chimeric receptor is capable of mediating osteoclast formation and we expressed the chimeric receptor in a R. K. S.L. J. PubMed Scopus Google Scholar, S. N. S. S.L. PubMed Scopus Google that is also in osteoclast formation and we used from and mice to of signaling TNF Glaccum M.B. C. C.R. Charrier K. J. 1998; Google Scholar). derived from mice the the chimeric receptor and the the for the domain of demonstrated not only that the was expressed on the also that the of the the To the chimeric receptor is capable of mediating osteoclast the RANKL in and RANKL osteoclasts, that the RANK in the is functional importantly, and also osteoclasts, that the chimeric receptor is a to form osteoclasts in to and the also from of the in a of to the of signaling pathways J. T. N. N. A. S. T. Cell 2000; PubMed Scopus Google Scholar). these not as osteoclasts the of the that importantly, as in these mononuclear to form in the the formation of mononuclear in this not the potential of the as a to study RANK signaling. we used the of Our that as to mediate osteoclast formation not To osteoclasts the are capable of we bone Osteoclasts the approach bone as as the RANK these data that a domain to the and cytoplasmic of RANK is to mediate osteoclast formation and as a of as a for RANK signaling in osteoclast differentiation and function. RANK in and we used the chimeric receptor approach to RANK cytoplasmic motifs that mediate osteoclast formation and function. several that the RANK cytoplasmic domain six that to RANK B.R. R. Lee S.Y. M. Choi J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google PTM2, V. J. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, B.R. R. Lee S.Y. M. Choi J. Biol. 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Lacey D.L. Dunstan C.R. Solovyev I. Colombero A. Timms E. Tan H-L. Elliott G. Kelley M.J. Sarosi I. Wang L. Xia X.Z. Elliott R. Chiu L. Black T. Scully S. Capparelli C. Morony S. Shimamoto G. Bass M.B. Boyle W.J. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 3540-3545Crossref PubMed Scopus (1428) Google Scholar, B.R. D. N. Arron M. H. Choi Y. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google H. Lacey D.L. Dunstan C.R. Solovyev I. Colombero A. Timms E. Tan H-L. Elliott G. Kelley M.J. Sarosi I. Wang L. Xia X.Z. Elliott R. Chiu L. Black T. Scully S. Capparelli C. Morony S. Shimamoto G. Bass M.B. Boyle W.J. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 3540-3545Crossref PubMed Scopus (1428) Google Scholar, E. S. T. N. K. Udagawa N. T. Takahashi N. Suda T. J. 1999; Google H. Lacey D.L. Dunstan C.R. Solovyev I. Colombero A. Timms E. Tan H-L. Elliott G. Kelley M.J. Sarosi I. Wang L. Xia X.Z. Elliott R. Chiu L. Black T. Scully S. Capparelli C. Morony S. Shimamoto G. Bass M.B. Boyle W.J. Proc. 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Full Text Full Text PDF PubMed Scopus Google Scholar). we either the the for and the of the signaling pathways was by the the of of to that of the are in the of the pathway. the also to a of of and and and in to the of and was in the and and that more of in a role in activating the and pathway. a was also for p38 these data that the and osteoclast by activating these signaling we examined pathways of the three functional RANK motifs activates in by and in to to of and and and and and and that three RANK motifs are to pathway. Moreover, data that also three and p38 only p38 and not of the pathways PFQEP369-373 is in of and three PVQEET559-564 activates and p38 PVQEQG604-609 is only capable of activating the of RANKL by two bone groups (4Lacey D.L. Timms E. Tan H.L. Kelley M.J. Dunstan C.R. Burgess T. Elliott R. Colombero A. Elliott G. Scully S. Hsu H. Sullivan J Hawkins N. Davy E. Capparelli C. Eli A. Qian Y.X. Kaufman S. Sarosi I Shalhoub V. Senaldi G. Guo J. Delaney J. Boyle W.J. Cell. 1998; 93: 165-176Abstract Full Text Full Text PDF PubMed Scopus (4656) Google Scholar, 5Yasuda H. Shima N. Nakagawa N. Yamaguchi K. Kinosaki M. Mochizuki S. Tomoyasu A. Yano K. Goto M. Murakami A. Tsuda E. Morinaga T. Higashio K. Udagawa N. Takahashi N. Suda T. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 3597-3602Crossref PubMed Scopus (3592) Google and two groups D.M. Maraskovsky E. Billingsley W.L. Dougall W.C. Tometsko M.E. Roux E.R. Teepe M.C. DuBose R.F. Cosman D. Galibert L. Nature. 1997; 390: 175-179Crossref PubMed Scopus (1960) Google Scholar, 7Wong B.R. Rho J. Arron J. Robinson E. Orlinick J. Chao M Kalachikov S. Cayani E. Bartlett F.S. II I Frankel W.N. Lee S.Y. Choi Y. J. Biol. Chem. 1997; 272: 25190-25194Abstract Full Text Full Text PDF PubMed Scopus (918) Google in the late RANKL has been to play pivotal roles in such as bone (1Teitelbaum S.L. Science. 2000; 289: 1504-1508Crossref PubMed Scopus (3104) Google Scholar, 5Yasuda H. Shima N. Nakagawa N. Yamaguchi K. Kinosaki M. Mochizuki S. Tomoyasu A. Yano K. Goto M. Murakami A. Tsuda E. Morinaga T. Higashio K. Udagawa N. Takahashi N. Suda T. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 3597-3602Crossref PubMed Scopus (3592) Google function D.M. Maraskovsky E. Billingsley W.L. Dougall W.C. Tometsko M.E. Roux E.R. Teepe M.C. DuBose R.F. Cosman D. Galibert L. Nature. 1997; 390: 175-179Crossref PubMed Scopus (1960) Google Scholar, B.R. R. Choi Y. J. Biol. 1999; PubMed Scopus Google and development Y.Y. J. T. J. Elliott R. Scully S. R. Penninger J.M. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). has also been that RANKL its by binding to its receptor RANK, a member of the TNF receptor superfamily D.M. Maraskovsky E. Billingsley W.L. Dougall W.C. Tometsko M.E. Roux E.R. Teepe M.C. DuBose R.F. Cosman D. Galibert L. Nature. 1997; 390: 175-179Crossref PubMed Scopus (1960) Google Scholar). However, the intracellular signaling pathways in the in to RANKL have not been have the of RANK the and the in RANK cytoplasmic domain that H. Lacey D.L. Dunstan C.R. Solovyev I. Colombero A. Timms E. Tan H-L. Elliott G. Kelley M.J. Sarosi I. Wang L. Xia X.Z. Elliott R. Chiu L. Black T. Scully S. Capparelli C. Morony S. Shimamoto G. Bass M.B. Boyle W.J. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 3540-3545Crossref PubMed Scopus (1428) Google Scholar, V. J. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, B.R. R. Lee S.Y. M. Choi J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, Lee Lee J Lee 1999; PubMed Scopus Google Scholar, J. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, L. Tometsko M.E. D.M. Cosman D. Dougall W.C. J. Biol. 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Our study on of structural determinants in the RANK cytoplasmic domain that are in osteoclast formation and function. To we to study of RANK in by osteoclast this has been by a of in of the of a chimeric receptor approach R. K. S.L. J. PubMed Scopus Google Scholar, S. N. S. S.L. PubMed Scopus Google Moreover, the of study is that we a on RANK cytoplasmic motifs that such as osteoclast formation and bone Significantly, we revealed that RANK three distinct PVQEET559-564, and PVQEQG604-609 are capable of mediating osteoclast formation and function. PFQEP369-373 has been to a H. Arron M. T. D. M. M. K. S. Choi Y. H. Nature. PubMed Scopus Google Scholar). derived from this osteoclast formation H. Arron M. T. D. M. M. K. S. Choi Y. H. Nature. PubMed Scopus Google that this in osteoclast Our study that PFQEP369-373 a functional role not only in osteoclast formation also in osteoclast bone Moreover, we revealed that RANK two more motifs and PVQEQG604-609) that are to osteoclast formation and function. PVQEET559-564 and PVQEQG604-609 are more in osteoclast formation PFQEP369-373 and Tometsko M.E. Glaccum M. Cosman D. Dougall W.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google RANK cytoplasmic capable of mediating osteoclast formation and function by RANK these two functional motifs are in the functional RANK revealed by this the of the functional RANK we examined the of these motifs to several known signaling pathways by signaling study that three motifs are to in to pathways that these functional RANK motifs play distinct roles in intracellular signaling this that these functional motifs signaling by has been that PFQEP369-373 is a H. Arron M. T. D. M. M. K. S. Choi Y. H. Nature. PubMed Scopus Google Scholar). in data that PVQEET559-564 and PVQEQG604-609 L. Tometsko M.E. D.M. Cosman D. Dougall W.C. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). However, is to PVQEET559-564 and Galibert L. Tometsko M.E. D.M. Cosman D. Dougall W.C. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google that PVQEET559-564 and PVQEQG604-609 is capable of binding and in study demonstrated that RANK H. Lacey D.L. Dunstan C.R. Solovyev I. Colombero A. Timms E. Tan H-L. Elliott G. Kelley M.J. Sarosi I. Wang L. Xia X.Z. Elliott R. Chiu L. Black T. Scully S. Capparelli C. Morony S. Shimamoto G. Bass M.B. Boyle W.J. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 3540-3545Crossref PubMed Scopus (1428) Google Scholar). is in to that to these RANK motifs in intracellular signaling in osteoclast formation and function. demonstrated that the RANK motifs a distinct in osteoclast formation in the of and PVQEET559-564 and PVQEQG604-609 are more PFQEP369-373 in osteoclasts. Our signaling data revealed that these motifs in to mediate signaling pathways However, is that the in to form osteoclasts from to three pathways independently by in the S. Wang S.L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). these data that PVQEET559-564 and PVQEQG604-609 as pathways to osteoclast this more the signaling the osteoclast The identified functional RANK motifs have potential to further as therapeutic targets for bone osteoclasts. The of the has to develop OPG and as therapeutic to bone 2003; PubMed Scopus Google Scholar). However, both OPG and have a as therapeutic of the that RANKL not only a pivotal role in osteoclast formation and differentiation H. Lacey D.L. Dunstan C.R. Solovyev I. Colombero A. Timms E. Tan H-L. Elliott G. Kelley M.J. Sarosi I. Wang L. Xia X.Z. Elliott R. Chiu L. Black T. Scully S. Capparelli C. Morony S. Shimamoto G. Bass M.B. Boyle W.J. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 3540-3545Crossref PubMed Scopus (1428) Google is also a of such as the B.R. R. Choi Y. J. Biol. 1999; PubMed Scopus Google Scholar, B.R. R. Lee S.Y. H.L. Choi Y. J. 1997; PubMed Scopus Google and development Y.Y. J. T. J. Elliott R. Scully S. R. Penninger J.M. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). a of either OPG to bone potential on of role of the three RANK motifs in address these RANK motifs as targets for and bone such as osteoporosis.
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