Although recombinant human bone morphogenetic proteins (BMPs) are used locally for treating bone defects in humans, their systemic effect on bone augmentation has not been explored. We have previously demonstrated that demineralized bone (DB) from ovariectomized (OVX) rats cannot induce bone formation when implanted ectopically at the subcutaneous site. Here we showed in vitro that 17β-estradiol (E2) specifically induced expression of Bmp6 mRNA in MC3T3-E1 preosteoblastic cells and that bone extracts from OVX rats lack BMPs. Next we demonstrated that 125I-BMP-6 administered systemically accumulated in the skeleton and also restored the osteoinductive capacity of ectopically implanted DB from OVX rats. BMP-6 applied systemically to aged OVX rats significantly increased bone volume and mechanical characteristics of both the trabecular and cortical bone, the osteoblast surface, serum osteocalcin and osteoprotegerin levels, and decreased the osteoclast surface, serum C-telopeptide, and interleukin-6. E2 was significantly less effective, and was not synergistic with BMP-6. Animals that discontinued BMP-6 therapy maintained bone mineral density gains for another 12 weeks. BMP-6 increased in vivo the bone expression of Acvr-1, Bmpr1b, Smad5, alkaline phosphatase, and collagen type I and decreased expression of Bmp3 and BMP antagonists, chordin and cerberus. These results show, for the first time, that systemically administered BMP-6 restores the bone inductive capacity, microarchitecture, and quality of the skeleton in osteoporotic rats. Although recombinant human bone morphogenetic proteins (BMPs) are used locally for treating bone defects in humans, their systemic effect on bone augmentation has not been explored. We have previously demonstrated that demineralized bone (DB) from ovariectomized (OVX) rats cannot induce bone formation when implanted ectopically at the subcutaneous site. Here we showed in vitro that 17β-estradiol (E2) specifically induced expression of Bmp6 mRNA in MC3T3-E1 preosteoblastic cells and that bone extracts from OVX rats lack BMPs. Next we demonstrated that 125I-BMP-6 administered systemically accumulated in the skeleton and also restored the osteoinductive capacity of ectopically implanted DB from OVX rats. BMP-6 applied systemically to aged OVX rats significantly increased bone volume and mechanical characteristics of both the trabecular and cortical bone, the osteoblast surface, serum osteocalcin and osteoprotegerin levels, and decreased the osteoclast surface, serum C-telopeptide, and interleukin-6. E2 was significantly less effective, and was not synergistic with BMP-6. Animals that discontinued BMP-6 therapy maintained bone mineral density gains for another 12 weeks. BMP-6 increased in vivo the bone expression of Acvr-1, Bmpr1b, Smad5, alkaline phosphatase, and collagen type I and decreased expression of Bmp3 and BMP antagonists, chordin and cerberus. These results show, for the first time, that systemically administered BMP-6 restores the bone inductive capacity, microarchitecture, and quality of the skeleton in osteoporotic rats. Bone loss during aging and after menopause in women is known to result from an imbalance between bone formation and resorption leading to altered bone microarchitecture and excess bone fragility. Inferior bone strength and increased bone fracture rate of bone in patients with osteoporosis might be associated with decreased osteoinductive and thus self-regenerative bone capacity eventually due to the lower content of growth and differentiation factors including bone morphogenetic proteins in the bone extracellular matrix (1Cesnjaj M. Stavljenic A. Vukicevic S. Acta Orthop. Scand. 1991; 62: 471-475PubMed Google Scholar, 2Reddi A.H. Nat. Biotechnol. 1998; 16: 247-252Crossref PubMed Scopus (699) Google Scholar, 3Martinovic S. Simic P. Borovecki F. Vukicevic S. Vukicevic S. Sampath K. Bone Morphogenetic Proteins, Regeneration of Bone and Beyond. Birkhäuser Verlag, Basel2004: 45-72Crossref Google Scholar, 4Abe E. Yamamoto M. Taguchi Y. Lecka-Czernik B. O'Brien C. Economides A.N. Stahl N. Jilka R.L. Manolagas S.C. J. Bone Miner. Res. 2000; 15: 663-673Crossref PubMed Scopus (274) Google Scholar). Demineralized bone matrix (DBM) 2The abbreviations used are: DBM, demineralized bone matrix; OVX, ovariectomized;BMD,bonemineraldensity;CT,computerizedtomography;N,newton; ELISA, enzyme-linked immunosorbent assay; OPG, osteoprotegerin; IL, interleukin; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; ANOVA, analysis of variance; DTT, dithiothreitol; PTH, parathyroid hormone.2The abbreviations used are: DBM, demineralized bone matrix; OVX, ovariectomized;BMD,bonemineraldensity;CT,computerizedtomography;N,newton; ELISA, enzyme-linked immunosorbent assay; OPG, osteoprotegerin; IL, interleukin; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; ANOVA, analysis of variance; DTT, dithiothreitol; PTH, parathyroid hormone. induces de novo bone formation when implanted into the rat muscle (5Sampath T.K. Nathanson M.A. Reddi A.H. Proc. Natl. Acad. Sci. U. S. A. 1984; 81: 3419-3423Crossref PubMed Scopus (73) Google Scholar). On the contrary, DBM from OVX animals implanted into both normal and OVX rats induces only fibrous tissues suggesting that its decreased bone inducing activity is due to abnormal composition of bone from OVX rats and not to the 17β-estradiol (E2)-deficient microenvironment (1Cesnjaj M. Stavljenic A. Vukicevic S. Acta Orthop. Scand. 1991; 62: 471-475PubMed Google Scholar). Lack of specific signals needed for ectopic bone induction may, at least in part, explain diminished bone potency to heal fractures in osteoporotic patients (6Raisz L.G. Rodan G.A. Endocrinol. Metab. Clin. North Am. 2003; 32: 15-24Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar, 7Srivastava A.K. Vliet E.L. Lewiecki E.M. Maricic M. Abdelmalek A. Gluck O. Baylink D.J. Curr. Med. Res. Opin. 2005; 21: 1015-1026Crossref PubMed Scopus (76) Google Scholar). It has been demonstrated that fetal osteoblastic cell lines treated by E2 specifically express Bmp6 mRNA, whereas gene transcripts of other members of the BMP family are unaffected (8Rickard D.J. Hofbauer L.C. Bonde S.K. Gori F. Spelsberg T.C. Riggs B.L. J. Clin. Investig. 1998; 101: 413-422Crossref PubMed Scopus (84) Google Scholar). A functional relationship between E2 and BMP-6 was further suggested by E2 binding to the Bmp6 gene promotor (9Ong D.B. Colley S.M. Norman M.R. Kitazawa S. Tobias J.H. J. Bone Miner. Res. 2004; 19: 447-454Crossref PubMed Scopus (26) Google Scholar) and by increased BMP-6 immunostaining in bone marrow of mice treated with E2 (10Plant A. Tobias J.H. J. Bone Miner. Res. 2002; 17: 782-790Crossref PubMed Scopus (18) Google Scholar). Although numerous studies have unequivocally demonstrated that BMPs induce new bone formation locally in animals and humans, both ectopically and when implanted between bone ends in patients with delayed non-unions or acute fractures (11Friedlaender G.E. Vukicevic S. Sampath K. Bone morphogenetic proteins, Regeneration of Bone and Beyond. Birkhäuser Verlag, Basel2004: 157-163Crossref Google Scholar, 12Friedlaender G.E. Perry C.R. Cole J.D. Cook S.D. Cierny G. Muschler G.F. Zych G.A. Calhoun J.H. LaForte A.J. Yin S. J. Bone Joint Surg. 2001; 83: 151-158Crossref PubMed Scopus (113) Google Scholar), so far it has not been shown that a systemically administered recombinant BMP can effect the bone volume in OVX rats. In these studies we tested the effect of systemically administered recombinant BMP-6 on bone formation in aged OVX rats and showed for the first time that BMP-6 is a novel systemic bone anabolic agent and has a potential for treating bone loss in patients with osteoporosis. Demineralized Bone Matrix—Bone matrix was prepared from 6-month-old Sprague-Dawley rats, 3 months following OVX. After sacrifice, diaphyses of femurs and tibiae and and demineralized previously (5Sampath T.K. Nathanson M.A. Reddi A.H. Proc. Natl. Acad. Sci. U. S. A. 1984; 81: 3419-3423Crossref PubMed Scopus (73) Google Scholar). DBM from OVX rats was implanted in the of normal and OVX rats, with and of BMP-6 from to following following of DBM, and in with and for the of new and MC3T3-E1 and of in with fetal serum and at in a of and from MC3T3-E1 cells from at 3 in and growth was by with and with E2 at for 12 and the time was and by or Sprague-Dawley rats to OVX. Animals with an of at of animals to during the in the rats from the and for a of to months following to the of BMP-6 at of and was the rat or a for or In and OVX rats used in OVX OVX BMP-6 3 OVX BMP-6 3 OVX BMP-6 3 OVX E2 3 and OVX E2 3 BMP-6 3 12 months following OVX and for 12 OVX OVX BMP-6 3 for 3 and 3 OVX BMP-6 was OVX BMP-6 3 OVX E2 3 and OVX therapy for months following OVX and for months including the first and OVX OVX BMP-6 3 OVX BMP-6 3 and OVX BMP-6 months following OVX and for and by the and the of and BMP-6 was in cells previously E. C. Sampath T.K. J. PubMed Scopus Google Scholar, K. J. PubMed Scopus (76) Google Scholar). by a was to and the was and of was a that been with and was at a rate of was with of BMP-6 was at a of and and of BMP-6 BMP-6 was with of a of the Sampath T.K. Vukicevic S. 2000; Full Text Full Text PDF PubMed Google Scholar, S. N. A. B. S. J. M. M. Stavljenic A. Sampath T.K. J. Clin. Investig. 1998; PubMed Scopus Google Scholar). on a was used to BMP-6 from the was with and specific activity of the 125I-BMP-6 used in was a of 125I-BMP-6 at a of with the activity of volume was Animals and following and was in a of 125I-BMP-6 by tissues during the time was of 125I-BMP-6 of of Bone from and OVX and from and OVX rats in and into a with a of bone at with and a of was and T.K. C. E. J. Full Text PDF PubMed Google Scholar). was in and by a proteins with and in at a rate of by was and and at was on a to the of PubMed Scopus Google Scholar). in for 3 with or to the was the and with a BMP-6 and S. P. Reddi A.H. Sampath T.K. Res. PubMed Scopus Google Scholar). and used a with the In and Bone by the animals for bone density by S. S.D. Med. 2002; Google Scholar). the of the animals and by and and in and and the used for of bone mineral content and by Scopus Google Scholar) with was was and was and the bone bone mineral and bone density of and and the of femurs and tibiae femurs by a with and of the bone, and cortical previously P. J. 1998; PubMed Scopus Google Scholar, O. G. C. J. Clin. Investig. PubMed Scopus Google Scholar). and the used in these from P. B. PubMed Scopus Google Scholar). was in in the M. K. K. 1998; PubMed Scopus Google Scholar). of bone was the trabecular bone volume trabecular trabecular and trabecular on the by A. J. P. J. Bone Miner. Res. PubMed Scopus Google Scholar). trabecular bone and the with the M. M. M. G. PubMed Scopus Google Scholar, P. PubMed Scopus Google Scholar). and a subcutaneous of the at at and femurs at prepared for and a analysis and previously S.M. J. Bone Miner. Res. PubMed Scopus Google Scholar, B. Vukicevic S. M. Stavljenic A. J. Bone Miner. Res. PubMed Scopus (26) Google Scholar, S. B. Stavljenic A. J. Bone Miner. Res. PubMed Scopus Google Scholar). for in in and with and to potential a of mechanical on the of the was used to the mechanical of the of the was to to at a rate of by and D.B. PubMed Scopus Google Scholar), a cell and from the of the was used to the mechanical of bone in the marrow of the previously J. Bone Miner. Res. PubMed Scopus Google Scholar, M. J. Clin. Investig. PubMed Scopus Google Scholar). and bone formation and resorption by of osteocalcin was by rat osteocalcin of was by osteoprotegerin in serum was by the rat of was by an following by the of C-telopeptide, OPG, and and and was with and was from of with by the with of are shown in in a for by in in and with of used for gene expression analysis are for rat whereas used for of the MC3T3-E1 cell in in vitro in a new of from rat bone with of to the expression of was a in a 2001; PubMed Scopus Google Scholar). of are shown in of was and was used to the transcripts used a are of the expression of tested with and the time with with OVX and of with in gene expression with OVX and Bone from OVX in extracts from normal and OVX rats by analysis following with bone extracts from normal rats, OVX animals of and suggesting that E2 results with decreased of BMPs in that the lack of capacity of DBM from OVX rats to new bone at an ectopic in both normal and OVX rats be at least in due to DBM (1Cesnjaj M. Stavljenic A. Vukicevic S. Acta Orthop. Scand. 1991; 62: 471-475PubMed Google Scholar). BMP-6 Bone by to DBM from OVX of BMP-6 tested by following subcutaneous of DBM from OVX rats into both normal and OVX rats. bone formation was in an to the induced by DBM from normal rats and These results following systemic of DBM from OVX rats, new bone induction capacity, the potential in both normal and OVX rats. A result was when and thus DBM from normal rats was implanted into rats from to with BMP-6 not These results to systemic of BMP-6 is in bone volume in aged rats months following OVX. and of to the of BMP-6 on the skeleton we tested its and serum of 125I-BMP-6 after by a of was in after a of of 125I-BMP-6 in the rat increased during the first following and decreased in the following whereas the of 125I-BMP-6 in the increased and decreased the of 125I-BMP-6 in was of the applied of the at and to of the applied at following of 125I-BMP-6 in the was of the applied of at following and to of the applied at following analysis demonstrated that 125I-BMP-6 in the at after not E2 of mRNA in MC3T3-E1 in to of E2 a in these studies we to its specific effect on Bmp6 mRNA expression in osteoblastic cells in MC3T3-E1 express and during differentiation and in vitro bone formation S. Simic P. Borovecki F. Vukicevic S. Vukicevic S. Sampath K. Bone Morphogenetic Proteins, Regeneration of Bone and Beyond. Birkhäuser Verlag, Basel2004: 45-72Crossref Google Scholar). of E2 to cell the expression of and specifically induced the expression of Bmp6 transcripts in a of bone on of not not Bmp6 was thus of the of and in in vitro E2 the expression of specific BMP by MC3T3-E1 cells bone morphogenetic and and MC3T3-E1 cells treated with E2 A type a specific BMP type I to be used by BMP-6 in not BMP-6 Bone in OVX months following OVX rats treated for months with BMP-6 and the was restored of rats the and at 12 following therapy and with OVX, and animals and between BMP-6 of and the of treated rats decreased by of the showed an of at 12 following BMP-6 not vivo of and increased in rats treated with of a E2 was less BMP-6 in not of femurs showed that was and the bone mineral content was in rats with OVX rats. bone mineral content was for cortical bone mineral for and the cortical at with OVX rats bone in femurs the trabecular bone by BMP-6 of the tibiae showed a a effect of BMP-6 on the cortical bone of the skeleton not of the in aged OVX rats treated with BMP-6 and E2 Animals treated for 3 months following 12 months of OVX in bone mineral bone mineral cortical bone mineral and cortical are from from from from from from from from BMP-6 from from from from from in a new of femurs showed that the bone volume of rats treated with of BMP-6 was increased with OVX animals and increased with rats E2 3 and trabecular was in BMP-6 and in rats trabecular was increased in with OVX rats, and was and in and trabecular was decreased in rats BMP-6 therapy increased the density and decreased the in of the at bone and volume of rats. analysis of the showed increased increased trabecular increased trabecular and decreased trabecular in rats suggested that the trabecular bone of the the of to the systemic of BMP-6 with volume and trabecular microarchitecture of in aged OVX rats treated with BMP-6 and E2 by Animals treated for 3 months following 12 months of OVX for trabecular bone trabecular trabecular trabecular are from from from from 3 from from from from from 3 from from 3 in a new was used to the mechanical of the and and in animals with OVX rats. from animals in animals was increased by in rats with rats was used to the mechanical characteristics of of the of and increased in rats with OVX animals strength showed the BMP-6 the trabecular bone with OVX not the mechanical to by of the from BMP-6 treated aged OVX rats Animals treated for 3 months following 12 months of OVX in are was to to and are with to OVX and rats by on mechanical of trabecular and strength are with to OVX and rats by and are with to OVX and rats by on mechanical of trabecular and strength are with to OVX and rats by in a new showed that bone volume and trabecular of femurs for and in animals bone showed an increased mineral rate at and bone formation volume at in rats, whereas E2 decreased the bone formation rate by BMP-6 both increased the osteoblast for and decreased the osteoclast for E2 decreased the osteoclast for not have an effect on the osteoblast bone formation and mechanical of from both increased of and increased extracellular matrix E2 therapy and in not the of rats was in E2 and in was not from OVX rats not not only rats treated with E2 or E2 and BMP-6 increased not of bone marrow and of the at the of BMP-6 BMP-6 and E2 on Bone in OVX treated with E2 at 12 following therapy OVX animals both BMP-6 and E2 to OVX rats, at 12 increased by in rats treated with E2 and BMP-6 was not from rats treated with BMP-6 E2 effect on cortical and trabecular whereas a of E2 and BMP-6 increased cortical by an effect on trabecular These results that E2 not have an effect on the bone in aged OVX rats with BMP-6. of BMP-6 on months following BMP-6 therapy the expression of and Bmpr1b, BMP Smad5, a in the BMP was increased E2 the expression of and and effect on and Bmp3 expression was increased following OVX and by both BMP-6 and E2 therapy On the other OVX the expression of Bmp6 in whereas E2 increased the Bmp6 expression expression was with both BMP-6 and E2 BMP-6 increased the expression of alkaline and collagen type I the expression of of BMP antagonists, chordin and was decreased in rat femurs treated with BMP-6. expression of was decreased following OVX and increased to normal following BMP-6 therapy On the contrary, the expression of was increased following OVX, BMP-6 therapy further increased whereas E2 effect BMP-6 at a of increased the serum osteocalcin a bone formation with OVX whereas E2 not have an effect lower in rats treated with BMP-6 that BMP-6 the activity of BMP-6 increased the serum with OVX animals to lower osteoclast in rats BMP-6 may, bone formation and bone in explain its anabolic bone BMP-6 of in and decreased serum following a BMP-6 the expression of in the to with OVX rats suggesting an by BMP-6 might the osteoclast of Bone in OVX by further bone following BMP-6 therapy was BMP-6 was to aged OVX rats for 12 and Animals into treated with and the BMP-6 was at and BMP-6 therapy the of months increased the with both OVX and rats that of from the of in animals treated with BMP-6 at at 12 and with OVX rats, whereas at and not In rats treated with E2 following the BMP-6 therapy gains Animals therapy maintained the the and showed a to in OVX rats We that animals that discontinued BMP-6 therapy maintained the gains for another 12 whereas with E2 maintained the the of the vivo of the and to the in vivo results not BMP-6 the in Bone in OVX for the BMP-6 aged OVX rats months following OVX administered BMP-6 less at lower following the of animals showed of with both OVX and animals of BMP-6 increased the by of and 3 increased the at and aged rats bone volume in an to animals treated with BMP-6 not at the of the the was a at the bone that a time to the of to the of BMP-6. In these studies we that systemically administered BMP-6 in aged OVX rats has a anabolic effect significantly the bone in vivo and vivo bone that BMP-6 restores trabecular bone of the skeleton and the cortical bone, whereas only a of the trabecular bone in and increased in rats. with BMP-6 serum and serum osteocalcin and osteoprotegerin levels, suggesting of bone formation from bone only E2 and parathyroid have on the and of the morphogenetic and and K. P. P. Nat. 17: PubMed Scopus Google Scholar, K. M. M. J. Nat. PubMed Scopus Google Scholar). are by of the and defects of and the normal skeleton K. P. P. Nat. 17: PubMed Scopus Google Scholar, K. M. M. J. Nat. PubMed Scopus Google Scholar). is by a in a whereas in is an in the leading to far the is the only anabolic bone agent that trabecular bone the cortical bone M. J.D. 2000; PubMed Scopus Google Scholar) and cortical M. M. A. J. J. Bone Miner. 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