Sostdc1 Suppression in the Absence of Sclerostin Potentiates Anabolic Action of Cortical Bone in Mice

Choi, Roy B.; Hoggatt, April M.; Horan, Daniel J.; Rogers, Emily Z.; Loots, Gabriela G.; Robling, Alexander G.

doi:10.1002/jbmr.4798

Sostdc1 Suppression in the Absence of Sclerostin Potentiates Anabolic Action of Cortical Bone in Mice

Journal Article · Thu Mar 09 00:00:00 EST 2023 · Journal of Bone and Mineral Research

DOI:https://doi.org/10.1002/jbmr.4798· OSTI ID:1963109

Choi, Roy B.; Hoggatt, April M.; Horan, Daniel J.; Rogers, Emily Z.; Loots, Gabriela G.;

ABSTRACT

The development of Wnt-based osteoanabolic agents has progressed rapidly in recent years, given the potent effects of Wnt modulation on bone homeostasis. Simultaneous pharmacologic inhibition of the Wnt antagonists sclerostin and Dkk1 can be optimized to create potentiated effects in the cancellous bone compartment. We looked for other candidates that might be co-inhibited along with sclerostin to potentiate the effects in the cortical compartment. Sostdc1 (Wise), like sclerostin and Dkk1, also binds and inhibits Lrp5/6 coreceptors to impair canonical Wnt signaling, but Sostdc1 has greater effects in the cortical bone. To test this concept, we deleted Sostdc1 and Sost from mice and measured the skeletal effects in cortical and cancellous compartments individually. Sost deletion alone produced high bone mass in all compartments, whereas Sostdc1 deletion alone had no measurable effects on either envelope. Mice with codeletion of Sostdc1 and Sost had high bone mass and increased cortical properties (bone mass, formation rates, mechanical properties), but only among males. Combined administration of sclerostin antibody and Sostdc1 antibody in wild-type female mice produced potentiation of cortical bone gain despite no effect of Sostdc1 antibody alone. In conclusion, Sostdc1 inhibition/deletion can work in concert with sclerostin deficiency to improve cortical bone properties. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

View Journal Article

Research Organization:: Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)

Sponsoring Organization:: National Institutes of Health (NIH); US Department of Veterans Affairs; USDOE

Grant/Contract Number:: AC52-07NA27344

OSTI ID:: 1963109

Alternate ID(s):: OSTI ID: 2424286
OSTI ID: 1963110

Journal Information:: Journal of Bone and Mineral Research, Journal Name: Journal of Bone and Mineral Research Journal Issue: 5 Vol. 38; ISSN 0884-0431

Publisher:: Oxford University PressCopyright Statement

Country of Publication:: United States

Language:: English

References (35)

Improving Bone Health by Optimizing the Anabolic Action of Wnt Inhibitor Multitargeting Choi, Roy B.; Bullock, Whitney A.; Hoggatt, April M. JBMR Plus, Vol. 5, Issue 5 https://doi.org/10.1002/jbm4.10462	journal	May 2021
Guidelines for assessment of bone microstructure in rodents using micro-computed tomography Bouxsein, Mary L.; Boyd, Stephen K.; Christiansen, Blaine A. Journal of Bone and Mineral Research, Vol. 25, Issue 7 https://doi.org/10.1002/jbmr.141	journal	June 2010
Standardized nomenclature, symbols, and units for bone histomorphometry: A 2012 update of the report of the ASBMR Histomorphometry Nomenclature Committee Dempster, David W.; Compston, Juliet E.; Drezner, Marc K. Journal of Bone and Mineral Research, Vol. 28, Issue 1 https://doi.org/10.1002/jbmr.1805	journal	December 2012
Inhibition of sclerostin by monoclonal antibody increases bone formation, bone mass, and bone strength in aged male rats Li, Xiaodong; Warmington, Kelly S.; Niu, Qing-Tian Journal of Bone and Mineral Research, Vol. 25, Issue 12 https://doi.org/10.1002/jbmr.182	journal	July 2010
Notum Deletion From Late‐Stage Skeletal Cells Increases Cortical Bone Formation and Potentiates Skeletal Effects of Sclerostin Inhibition Choi, Roy B.; Bullock, Whitney A.; Hoggatt, April M. Journal of Bone and Mineral Research, Vol. 36, Issue 12 https://doi.org/10.1002/jbmr.4411	journal	July 2021
US population aging and demand for inpatient services Pallin, Daniel J.; Espinola, Janice A.; Camargo, Carlos A. Journal of Hospital Medicine, Vol. 9, Issue 3 https://doi.org/10.1002/jhm.2145	journal	January 2014
Cortical bone development, maintenance and porosity: genetic alterations in humans and mice influencing chondrocytes, osteoclasts, osteoblasts and osteocytes Isojima, Tsuyoshi; Sims, Natalie A. Cellular and Molecular Life Sciences, Vol. 78, Issue 15 https://doi.org/10.1007/s00018-021-03884-w	journal	July 2021
Contribution of the sclerostin domain-containing protein 1 (SOSTDC1) gene to normal variation of peak bone mineral density in Chinese women and men He, Jin-Wei; Yue, Hua; Hu, Wei-Wei Journal of Bone and Mineral Metabolism, Vol. 29, Issue 5 https://doi.org/10.1007/s00774-010-0253-5	journal	January 2011
Basic biomechanical measurements of bone: A tutorial Turner, C. H.; Burr, D. B. Bone, Vol. 14, Issue 4 https://doi.org/10.1016/8756-3282(93)90081-K	journal	July 1993
USAG-1: a bone morphogenetic protein antagonist abundantly expressed in the kidney Yanagita, Motoko; Oka, Masako; Watabe, Tetsuro Biochemical and Biophysical Research Communications, Vol. 316, Issue 2 https://doi.org/10.1016/j.bbrc.2004.02.075	journal	April 2004
Sostdc1 deficiency accelerates fracture healing by promoting the expansion of periosteal mesenchymal stem cells Collette, Nicole M.; Yee, Cristal S.; Hum, Nicholas R. Bone, Vol. 88 https://doi.org/10.1016/j.bone.2016.04.005	journal	July 2016
Induction of Lrp5 HBM-causing mutations in Cathepsin-K expressing cells alters bone metabolism Kang, Kyung Shin; Hong, Jung Min; Horan, Daniel J. Bone, Vol. 120 https://doi.org/10.1016/j.bone.2018.10.007	journal	March 2019
Sostdc1: A soluble BMP and Wnt antagonist that is induced by the interaction between myeloma cells and osteoblast lineage cells Faraahi, Z.; Baud'huin, M.; Croucher, P. I. Bone, Vol. 122 https://doi.org/10.1016/j.bone.2019.02.012	journal	May 2019
Lrp4 Mediates Bone Homeostasis and Mechanotransduction through Interaction with Sclerostin In Vivo Bullock, Whitney A.; Hoggatt, April M.; Horan, Daniel J. iScience, Vol. 20 https://doi.org/10.1016/j.isci.2019.09.023	journal	October 2019
Genetic evidence that SOST inhibits WNT signaling in the limb Collette, Nicole M.; Genetos, Damian C.; Murugesh, Deepa Developmental Biology, Vol. 342, Issue 2 https://doi.org/10.1016/j.ydbio.2010.03.021	journal	June 2010
Evolution of the DAN gene family in vertebrates Opazo, Juan C.; Hoffmann, Federico G.; Zavala, Kattina Developmental Biology, Vol. 482 https://doi.org/10.1016/j.ydbio.2021.12.002	journal	February 2022
A bispecific antibody targeting sclerostin and DKK-1 promotes bone mass accrual and fracture repair Florio, Monica; Gunasekaran, Kannan; Stolina, Marina Nature Communications, Vol. 7, Issue 1 https://doi.org/10.1038/ncomms11505	journal	May 2016
Characterization of the different oligomeric states of the DAN family antagonists SOSTDC1 and SOST Gipson, Gregory R.; Kattamuri, Chandramohan; Czepnik, Magdalena Biochemical Journal, Vol. 477, Issue 17 https://doi.org/10.1042/BCJ20200552	journal	September 2020
Cortical-Bone Fragility — Insights from sFRP4 Deficiency in Pyle’s Disease Simsek Kiper, Pelin O.; Saito, Hiroaki; Gori, Francesca New England Journal of Medicine, Vol. 374, Issue 26 https://doi.org/10.1056/NEJMoa1509342	journal	June 2016
Conditionals by inversion provide a universal method for the generation of conditional alleles Economides, Aris N.; Frendewey, David; Yang, Peter Proceedings of the National Academy of Sciences, Vol. 110, Issue 34 https://doi.org/10.1073/pnas.1217812110	journal	August 2013
Sclerostin Is a Novel Secreted Osteoclast-derived Bone Morphogenetic Protein Antagonist with Unique Ligand Specificity Kusu, Naoki; Laurikkala, Johanna; Imanishi, Mayumi Journal of Biological Chemistry, Vol. 278, Issue 26 https://doi.org/10.1074/jbc.M301716200	journal	April 2003
Regulation of Mammalian Tooth Cusp Patterning by Ectodin Kassai, Y. Science, Vol. 309, Issue 5743 https://doi.org/10.1126/science.1116848	journal	September 2005
Uterine sensitization-associated gene-1 (USAG-1), a novel BMP antagonist expressed in the kidney, accelerates tubular injury Yanagita, M. Journal of Clinical Investigation, Vol. 116, Issue 1 https://doi.org/10.1172/JCI25445	journal	December 2005
Loss of the BMP antagonist USAG-1 ameliorates disease in a mouse model of the progressive hereditary kidney disease Alport syndrome Tanaka, Mari; Asada, Misako; Higashi, Atsuko Y. Journal of Clinical Investigation, Vol. 120, Issue 3 https://doi.org/10.1172/JCI39569	journal	March 2010
Sclerostin neutralization unleashes the osteoanabolic effects of Dkk1 inhibition Witcher, Phillip C.; Miner, Sara E.; Horan, Daniel J. JCI Insight, Vol. 3, Issue 11 https://doi.org/10.1172/jci.insight.98673	journal	June 2018
Shh Plays an Inhibitory Role in Cusp Patterning by Regulation of Sostdc1 Kim, J.; Ahn, Y.; Adasooriya, D. Journal of Dental Research, Vol. 98, Issue 1 https://doi.org/10.1177/0022034518803095	journal	October 2018
Inhibition of Wnt signaling by Wise (Sostdc1) and negative feedback from Shh controls tooth number and patterning Ahn, Y.; Sanderson, B. W.; Klein, O. D. Development, Vol. 137, Issue 19 https://doi.org/10.1242/dev.054668	journal	August 2010
Bone Density Ligand, Sclerostin, Directly Interacts With LRP5 but Not LRP5G171V to Modulate Wnt Activity Ellies, Debra L.; Viviano, Beth; McCarthy, John Journal of Bone and Mineral Research, Vol. 21, Issue 11 https://doi.org/10.1359/jbmr.060810	journal	August 2006
Wnt10b Increases Postnatal Bone Formation by Enhancing Osteoblast Differentiation Bennett, Christina N.; Ouyang, Hongjiao; Ma, Yanfei L. Journal of Bone and Mineral Research, Vol. 22, Issue 12 https://doi.org/10.1359/jbmr.070810	journal	August 2007
WNT16 Influences Bone Mineral Density, Cortical Bone Thickness, Bone Strength, and Osteoporotic Fracture Risk Zheng, Hou-Feng; Tobias, Jon H.; Duncan, Emma PLoS Genetics, Vol. 8, Issue 7 https://doi.org/10.1371/journal.pgen.1002745	journal	July 2012
Lrp4 Modulates Extracellular Integration of Cell Signaling Pathways in Development Ohazama, Atsushi; Johnson, Eric B.; Ota, Masato S. PLoS ONE, Vol. 3, Issue 12 https://doi.org/10.1371/journal.pone.0004092	journal	December 2008
Anti-Sclerostin Antibody Inhibits Internalization of Sclerostin and Sclerostin-Mediated Antagonism of Wnt/LRP6 Signaling van Dinther, Maarten; Zhang, Juan; Weidauer, Stella E. PLoS ONE, Vol. 8, Issue 4 https://doi.org/10.1371/journal.pone.0062295	journal	April 2013
Antagonistic Functions of USAG-1 and RUNX2 during Tooth Development Togo, Yumiko; Takahashi, Katsu; Saito, Kazuyuki PLOS ONE, Vol. 11, Issue 8 https://doi.org/10.1371/journal.pone.0161067	journal	August 2016
Targeting Sclerostin and Dkk1 at Optimized Proportions of Low-Dose Antibody Achieves Similar Skeletal Benefits to Higher-Dose Sclerostin Targeting in the Mature Adult and Aged Skeleton Choi, Roy B.; Hoggatt, April M.; Horan, Daniel J. Aging and disease, Vol. 13, Issue 6 https://doi.org/10.14336/AD.2022.0315	journal	January 2022
Inhibition of WISE Preserves Renal Allograft Function Qian, Xueming; Yuan, Xiaodong; Vonderfecht, Steven Journal of the American Society of Nephrology, Vol. 24, Issue 1 https://doi.org/10.1681/ASN.2012010012	journal	January 2013

Similar Records

Sclerostin neutralization unleashes the osteoanabolic effects of Dkk1 inhibition [Genetic disruption of compensatory WNT inhibitor expression reveals a context-dependent, highly osteoanabolic role for DKK1 inhibition in the skeleton]

Journal Article · Wed Jun 06 20:00:00 EDT 2018 · JCI Insight · OSTI ID:1527294

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
Endocrinology & Metabolism
Wnt
Sclerostin
Sost
Sostdc1
Wise
Ectodin
Bone Anabolism
Osteoporosis

Sostdc1 Suppression in the Absence of Sclerostin Potentiates Anabolic Action of Cortical Bone in Mice

Citation Formats

References (35)

Similar Records

Related Subjects