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      • Record: found
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      Decreased osteoprogenitor proliferation precedes attenuation of cancellous bone formation in ovariectomized rats treated with sclerostin antibody

      research-article
      Author(s): a , * , b , c , c , a , a , 1 , d , 2 , a
      Publication date (Electronic):
      Journal: Bone Reports
      Publisher: Elsevier
      Keywords: ANOVA, analysis of variance, BrdU, 5-bromo-2′-deoxyuridine, CDKN1A, cyclin-dependent kinase inhibitor 1A, CDKN2A, CDKN inhibitor 2A, CE, coefficient of error, CV, coefficient of variation, D, day, E2F1, E2F transcription factor 1, FOXM1, Forkhead box protein M1, MS/BS, mineralizing surface per bone surface, MYC, v-myc avian myelocytomatosis viral oncogene homolog, MYCN, MYC neuroblastoma-derived homolog, OB, osteoblast(s), Ob.N, OB number, OCy, osteocyte(s), OP, osteoprogenitor(s), OVX, ovariectomized, PROBE, precision range of an optimally balanced estimator, RB1, retinoblastoma protein 1, RUNX2, Runt-related transcription factor 2, Scl-Ab, sclerostin antibody, Scl-AbVI, 50 mg/kg of a Scl-Ab, SURS, systematic uniform random sampling, TP53, tumor protein p53, VEH, vehicle, Osteoporosis, Anabolics, Cell signaling, Osteoprogenitors, Wnt signaling, Bone

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          Abstract

          Sclerostin antibody (Scl-Ab) stimulates bone formation, which with long-term treatment, attenuates over time. The cellular and molecular mechanisms responsible for the attenuation of bone formation are not well understood, but in aged ovariectomized (OVX) rats, the reduction in vertebral cancellous bone formation is preceded by a reduction in osteoprogenitor (OP) number and significant induction of signaling pathways known to suppress mitogenesis and cell cycle progression in the osteocyte (OCy) (Taylor et al., 2016). To determine if the reduction in OP number is associated with a decrease in proliferation, aged OVX rats were administered vehicle or Scl-Ab for 9 or 29 days and implanted with continuous-delivery 5-bromo-2′-deoxyuridine (BrdU) mini-osmotic pumps 5 days prior to necropsy. The total number of BrdU-labeled osteoblasts (OB) was quantified in vertebral cancellous bone to indirectly assess the effects of Scl-Ab treatment on OP proliferation at the time of activation of modeling-based bone formation at day 9 and at the time of maximal mineralizing surface, initial decrease in OP number, and transcriptional changes in the OCy at day 29. Compared with vehicle, Scl-Ab resulted in an increase in the total number of BrdU-positive OB (+260%) at day 9 that decreased with continued treatment (+50%) at day 29. These differences in proliferation occurred at time points when the increase in total OB number was significant and similar in magnitude. These findings suggest that reduced OP proliferation contributes to the decrease in OP numbers, an effect that would limit the OB pool and contribute to the attenuation of bone formation that occurs with long-term Scl-Ab treatment.

          Highlights

          • •

            Sclerostin antibody stimulates bone formation (BF) that attenuates over time.

          • •

            Osteoprogenitor (OP) proliferation increases early with treatment.

          • •

            Attenuation of BF is preceded by a decrease in OP proliferation.

          • •

            Decrease is coincident with molecular signaling consistent with cell cycle arrest.

          • •

            Decreased OP proliferation contributes to the attenuation of BF.

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          Most cited references18

          • Record: found
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          • Article: not found

          The unbiased estimation of number and sizes of arbitrary particles using the disector.

          D Sterio (1984)
          A three-dimensional counting rule and its integral test system, the disector, for obtaining unbiased estimates of the number of arbitrary particles in a specimen is presented. Used in combination with ordinary and recently developed stereological methods unbiased estimates of various mean particle sizes and the variance of particle volume are obtainable on sets of two parallel sections with a known separation. The same principle allows the unbiased estimation of the distribution of individual particle volumes in sets of serial sections.
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            Notes on the estimation of the numerical density of arbitrary profiles: the edge effect

            Hans Gundersen (1977)
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              Stereology of arbitrary particles. A review of unbiased number and size estimators and the presentation of some new ones, in memory of William R. Thompson.

              H J Gundersen (1986)
              This paper deals with isolated, countable items, often termed particles, in three-dimensional space. Its substance is the unbiased stereological estimation of the number, height, surface and volume of such particles without any assumptions about their shape. The full range of estimators is described, some of them for the first time, some in an improved form, several in more than one version, and all of them under the single, absolute requirement that one can in fact identify what one is quantifying on sections. In terms of the minimal number of sections for the analysis, the estimators may be classified as follows: On a single section it is possible to estimate vV, the mean volume of particles in the volume-weighted or 'sieving'-distribution. On two parallel sections, separated by a known distance, estimators exist of particle number and of all mean sizes (height, surface and volume) in the ordinary number distribution, as well as of SDN(v), the standard deviation in the number distribution of particle volumes. If the containing space is relatively transparent the sections may be two optical sections within one thick physical section. On a stack of parallel sections, at least as high as the largest particle, and separated by known distances, one can get twelve mean sizes and twelve distributions of individual sizes: all combinations of three sizes: height, surface and volume in four different types of distributions: number, height, surface and volume. Fulfilling the sampling requirements of the above two estimation principles it has been shown very recently that by combining them one may even estimate mean sizes and number of arbitrary particles in a stack of sections with constant but unknown separation. Finally, a unique, unbiased estimator of the total number of items in a specimen is described for the use of which one need not measure the distance between sections, nor their thickness, nor the volume of the specimen, nor assume anything about shrinkage/swelling, sectioning compression or lost caps. It is the fractionator.
              Article 0 comments Cited 108 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Rogely Waite Boyce
                Danielle Brown
                Melanie Felx
                Nacera Mellal
                Kathrin Locher
                Ian Pyrah
                Michael S. Ominsky
                Scott Taylor
                Journal
                Journal ID (nlm-ta): Bone Rep
                Journal ID (iso-abbrev): Bone Rep
                Title: Bone Reports
                Publisher: Elsevier
                ISSN (Electronic): 2352-1872
                Publication date PMC-release: 03 March 2018
                Publication date Collection: June 2018
                Publication date (Electronic): 03 March 2018
                Volume: 8
                Pages: 90-94
                Affiliations
                [a ]Department of Comparative Biology and Safety Sciences, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States
                [b ]Charles River Laboratories, 4025 Stirrup Creek Drive, Suite 150, Durham, NC 27703, United States
                [c ]Charles River Laboratories, 22022 Transcanadienne, Senneville, QC H9X 3R3, Canada
                [d ]Department of CardioMetabolic Disorders, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States
                Author notes
                [* ]Corresponding author at: Department of Comparative Biology and Safety Sciences, Amgen Inc., One Amgen Center Drive, MS 29-2-A, Thousand Oaks, CA 91320, United States. rboyce@ 123456amgen.com
                [1]

                Current address: Seattle Genetics, 21823-30th Drive S.E., Bothell, WA 98021, United States.

                [2]

                Current address: Radius Health, Inc., 950 Winter St, Waltham, MA 02451, United States.

                Article
                Publisher ID: S2352-1872(18)30012-3
                DOI: 10.1016/j.bonr.2018.03.001
                PMC ID: 6020110
                SO-VID: ca3e5eef-1363-45a7-b593-df03e187f9d1
                Copyright © © 2018 Amgen Inc
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 29 August 2017
                Date revision received : 15 February 2018
                Date accepted : 2 March 2018
                Categories
                Subject: Article

                Keywords: anova, analysis of variance,brdu, 5-bromo-2′-deoxyuridine,cdkn1a, cyclin-dependent kinase inhibitor 1a,cdkn2a, cdkn inhibitor 2a,ce, coefficient of error,cv, coefficient of variation,d, day,e2f1, e2f transcription factor 1,foxm1, forkhead box protein m1,ms/bs, mineralizing surface per bone surface,myc, v-myc avian myelocytomatosis viral oncogene homolog,mycn, myc neuroblastoma-derived homolog,ob, osteoblast(s),ob.n, ob number,ocy, osteocyte(s),op, osteoprogenitor(s),ovx, ovariectomized,probe, precision range of an optimally balanced estimator,rb1, retinoblastoma protein 1,runx2, runt-related transcription factor 2,scl-ab, sclerostin antibody,scl-abvi, 50 mg/kg of a scl-ab,surs, systematic uniform random sampling,tp53, tumor protein p53,veh, vehicle,osteoporosis,anabolics,cell signaling,osteoprogenitors,wnt signaling,bone
                Data availability:
                Keywords: anova, analysis of variance, brdu, 5-bromo-2′-deoxyuridine, cdkn1a, cyclin-dependent kinase inhibitor 1a, cdkn2a, cdkn inhibitor 2a, ce, coefficient of error, cv, coefficient of variation, d, day, e2f1, e2f transcription factor 1, foxm1, forkhead box protein m1, ms/bs, mineralizing surface per bone surface, myc, v-myc avian myelocytomatosis viral oncogene homolog, mycn, myc neuroblastoma-derived homolog, ob, osteoblast(s), ob.n, ob number, ocy, osteocyte(s), op, osteoprogenitor(s), ovx, ovariectomized, probe, precision range of an optimally balanced estimator, rb1, retinoblastoma protein 1, runx2, runt-related transcription factor 2, scl-ab, sclerostin antibody, scl-abvi, 50 mg/kg of a scl-ab, surs, systematic uniform random sampling, tp53, tumor protein p53, veh, vehicle, osteoporosis, anabolics, cell signaling, osteoprogenitors, wnt signaling, bone

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