skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: 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]

Abstract

The WNT pathway has become an attractive target for skeletal therapies. High-bone-mass phenotypes in patients with loss-of-function mutations in the LRP5/6 inhibitor Sost (sclerosteosis), or in its downstream enhancer region (van Buchem disease), highlight the utility of targeting Sost/sclerostin to improve bone properties. Sclerostin-neutralizing antibody is highly osteoanabolic in animal models and in human clinical trials, but antibody-based inhibition of another potent LRP5/6 antagonist, Dkk1, is largely inefficacious for building bone in the unperturbed adult skeleton. In this work, we show that conditional deletion of Dkk1 from bone also has negligible effects on bone mass. Dkk1 inhibition increases Sost expression, suggesting a potential compensatory mechanism that might explain why Dkk1 suppression lacks anabolic action. To test this concept, we deleted Sost from osteocytes in, or administered sclerostin neutralizing antibody to, mice with a Dkk1-deficient skeleton. A robust anabolic response to Dkk1 deletion was manifest only when Sost/sclerostin was impaired. Whole-body DXA scans, μCT measurements of the femur and spine, histomorphometric measures of femoral bone formation rates, and biomechanical properties of whole bones confirmed the anabolic potential of Dkk1 inhibition in the absence of sclerostin. Moreover, combined administration of sclerostin and Dkk1 antibody in WT mice produced a synergistic effect onmore » bone gain that greatly exceeded individual or additive effects of the therapies, confirming the therapeutic potential of inhibiting multiple WNT antagonists for skeletal health. In conclusion, the osteoanabolic effects of Dkk1 inhibition can be realized if sclerostin upregulation is prevented. Anabolic therapies for patients with low bone mass might benefit from a strategy that accounts for the compensatory milieu of WNT inhibitors in bone tissue.« less

Authors:
 [1];  [1];  [1];  [1];  [1];  [2];  [1];  [3];  [4];  [5]
  1. Indiana Univ. School of Medicine, Indianapolis, IN (United States)
  2. Indiana Univ. School of Medicine, Indianapolis, IN (United States); Anderson Univ., Anderson, IN (United States)
  3. Rush Univ. Medical Center, Chicago, IL (United States)
  4. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Univ. of California Merced, Merced, CA (United States)
  5. Indiana Univ. School of Medicine, Indianapolis, IN (United States); Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, IN (United States); Purdue Univ., West Lafayette, IN (United States); Indiana Center for Musculoskeletal Health, Indianapolis,IN (United States)
Publication Date:
Research Org.:
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Sponsoring Org.:
USDOE National Nuclear Security Administration (NNSA); National Institutes of Health (NIH)
OSTI Identifier:
1527294
Report Number(s):
LLNL-JRNL-740438
Journal ID: ISSN 2379-3708; 894200
Grant/Contract Number:  
AC52-07NA27344
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
JCI Insight
Additional Journal Information:
Journal Volume: 3; Journal Issue: 11; Journal ID: ISSN 2379-3708
Publisher:
American Society for Clinical Investigation
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Witcher, Phillip C., Miner, Sara E., Horan, Daniel J., Bullock, Whitney A., Lim, Kyung-Eun, Kang, Kyung Shin, Adaniya, Alison L., Ross, Ryan D., Loots, Gabriela G., and Robling, Alexander G. 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]. United States: N. p., 2018. Web. doi:10.1172/jci.insight.98673.
Witcher, Phillip C., Miner, Sara E., Horan, Daniel J., Bullock, Whitney A., Lim, Kyung-Eun, Kang, Kyung Shin, Adaniya, Alison L., Ross, Ryan D., Loots, Gabriela G., & Robling, Alexander G. 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]. United States. https://doi.org/10.1172/jci.insight.98673
Witcher, Phillip C., Miner, Sara E., Horan, Daniel J., Bullock, Whitney A., Lim, Kyung-Eun, Kang, Kyung Shin, Adaniya, Alison L., Ross, Ryan D., Loots, Gabriela G., and Robling, Alexander G. Thu . "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]". United States. https://doi.org/10.1172/jci.insight.98673. https://www.osti.gov/servlets/purl/1527294.
@article{osti_1527294,
title = {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]},
author = {Witcher, Phillip C. and Miner, Sara E. and Horan, Daniel J. and Bullock, Whitney A. and Lim, Kyung-Eun and Kang, Kyung Shin and Adaniya, Alison L. and Ross, Ryan D. and Loots, Gabriela G. and Robling, Alexander G.},
abstractNote = {The WNT pathway has become an attractive target for skeletal therapies. High-bone-mass phenotypes in patients with loss-of-function mutations in the LRP5/6 inhibitor Sost (sclerosteosis), or in its downstream enhancer region (van Buchem disease), highlight the utility of targeting Sost/sclerostin to improve bone properties. Sclerostin-neutralizing antibody is highly osteoanabolic in animal models and in human clinical trials, but antibody-based inhibition of another potent LRP5/6 antagonist, Dkk1, is largely inefficacious for building bone in the unperturbed adult skeleton. In this work, we show that conditional deletion of Dkk1 from bone also has negligible effects on bone mass. Dkk1 inhibition increases Sost expression, suggesting a potential compensatory mechanism that might explain why Dkk1 suppression lacks anabolic action. To test this concept, we deleted Sost from osteocytes in, or administered sclerostin neutralizing antibody to, mice with a Dkk1-deficient skeleton. A robust anabolic response to Dkk1 deletion was manifest only when Sost/sclerostin was impaired. Whole-body DXA scans, μCT measurements of the femur and spine, histomorphometric measures of femoral bone formation rates, and biomechanical properties of whole bones confirmed the anabolic potential of Dkk1 inhibition in the absence of sclerostin. Moreover, combined administration of sclerostin and Dkk1 antibody in WT mice produced a synergistic effect on bone gain that greatly exceeded individual or additive effects of the therapies, confirming the therapeutic potential of inhibiting multiple WNT antagonists for skeletal health. In conclusion, the osteoanabolic effects of Dkk1 inhibition can be realized if sclerostin upregulation is prevented. Anabolic therapies for patients with low bone mass might benefit from a strategy that accounts for the compensatory milieu of WNT inhibitors in bone tissue.},
doi = {10.1172/jci.insight.98673},
url = {https://www.osti.gov/biblio/1527294}, journal = {JCI Insight},
issn = {2379-3708},
number = 11,
volume = 3,
place = {United States},
year = {2018},
month = {6}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Citation Metrics:
Cited by: 13 works
Citation information provided by
Web of Science

Save / Share:

Works referenced in this record:

Dickkopf-1 regulates bone formation in young growing rodents and upon traumatic injury
journal, October 2011


Sost deficiency led to a greater cortical bone formation response to mechanical loading and altered gene expression
journal, August 2017


Patients with sclerosteosis and disease carriers: Human models of the effect of sclerostin on bone turnover
journal, November 2011


Neutralisation of Dkk-1 protects from systemic bone loss during inflammation and reduces sclerostin expression
journal, September 2010


Six Novel Missense Mutations in the LDL Receptor-Related Protein 5 (LRP5) Gene in Different Conditions with an Increased Bone Density
journal, March 2003


Targeted Deletion of the Sclerostin Gene in Mice Results in Increased Bone Formation and Bone Strength
journal, February 2008


Basic biomechanical measurements of bone: A tutorial
journal, July 1993


The Lrp4 R1170Q Homozygous Knock-In Mouse Recapitulates the Bone Phenotype of Sclerosteosis in Humans
journal, August 2017


Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6
journal, June 2001


HBM Mice Have Altered Bone Matrix Composition and Improved Material Toughness
journal, May 2016


Dickkopf-related protein 1 (Dkk1) regulates the accumulation and function of myeloid derived suppressor cells in cancer
journal, April 2016


DMP1-targeted Cre Expression in Odontoblasts and Osteocytes
journal, April 2007


Dickkopf1 Is Required for Embryonic Head Induction and Limb Morphogenesis in the Mouse
journal, September 2001


The Anti-Osteoanabolic Function of Sclerostin Is Blunted in Mice Carrying a High Bone Mass Mutation of Lrp5: SCLEROSTIN INTERACTION WITH LRP5
journal, June 2015


Cortical-Bone Fragility — Insights from sFRP4 Deficiency in Pyle’s Disease
journal, June 2016


Genetic Approaches To Identifying Novel Osteoporosis Drug Targets: G
journal, August 2015


Osteoporosis-Pseudoglioma Syndrome: Three Novel Mutations in the <i>LRP5 </i>Gene and Response to Bisphosphonate Treatment
journal, January 2012


Lrp5 functions in bone to regulate bone mass
journal, May 2011


Sclerostin is a direct target of osteoblast-specific transcription factor osterix
journal, October 2010


A bispecific antibody targeting sclerostin and DKK-1 promotes bone mass accrual and fracture repair
journal, May 2016


Romosozumab Improves Bone Mass and Strength While Maintaining Bone Quality in Ovariectomized Cynomolgus Monkeys: ROMOSOZUMAB IMPROVES BONE MASS AND STRENGTH
journal, December 2016


Identification of differentially expressed genes between osteoblasts and osteocytes
journal, October 2009


TGF-β regulates sclerostin expression via the ECR5 enhancer
journal, March 2012


Wnt inhibitors Dkk1 and Sost are downstream targets of BMP signaling through the type IA receptor (BMPRIA) in osteoblasts
journal, December 2009


Secreted Wnt antagonist Dickkopf-1 controls kidney papilla development coordinated by Wnt-7b signalling
journal, May 2011


Bone mass is inversely proportional to Dkk1 levels in mice
journal, September 2007


Bone Overgrowth-associated Mutations in the LRP4 Gene Impair Sclerostin Facilitator Function
journal, April 2011


Reconstitution of a Frizzled8·Wnt3a·LRP6 Signaling Complex Reveals Multiple Wnt and Dkk1 Binding Sites on LRP6
journal, January 2010


Conditionals by inversion provide a universal method for the generation of conditional alleles
journal, August 2013


SOST is a target gene for PTH in bone
journal, August 2005


High Bone Mass-Causing Mutant LRP5 Receptors Are Resistant to Endogenous Inhibitors In Vivo
journal, September 2015


Targeting the LRP5 Pathway Improves Bone Properties in a Mouse Model of Osteogenesis Imperfecta: TARGETING LRP5 PATHWAY IMPROVES BONE PROPERTIES IN MOUSE MODEL OF OI
journal, September 2014


Dickkopf-1 is a master regulator of joint remodeling
journal, January 2007


Sclerostin Mediates Bone Response to Mechanical Unloading Through Antagonizing Wnt/β-Catenin Signaling
journal, October 2009


Parathyroid hormone (PTH)–induced bone gain is blunted in SOST overexpressing and deficient mice
journal, December 2009


Imaging the Material Properties of Bone Specimens Using Reflection-Based Infrared Microspectroscopy
journal, April 2012


The Binding Between Sclerostin and LRP5 is Altered by DKK1 and by High-Bone Mass LRP5 Mutations
journal, June 2008


Transcriptional control of Sost in bone
journal, March 2017


Bone Matrix Composition Following PTH Treatment is Not Dependent on Sclerostin Status
journal, October 2015


Romosozumab Treatment in Postmenopausal Women with Osteoporosis
journal, October 2016


Guidelines for assessment of bone microstructure in rodents using micro-computed tomography
journal, June 2010


Mechanical Stimulation of Bone in Vivo Reduces Osteocyte Expression of Sost/Sclerostin
journal, December 2007


Sclerostin Antibody Treatment Increases Bone Formation, Bone Mass, and Bone Strength in a Rat Model of Postmenopausal Osteoporosis*
journal, April 2009


Dkk1-mediated inhibition of Wnt signaling in bone results in osteopenia
journal, October 2006


Osteocyte control of bone formation via sclerostin, a novel BMP antagonist
journal, December 2003


Characterization of Dkk1 gene regulation by the osteoblast-specific transcription factor Osx
journal, April 2012


Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse
journal, January 2001


Serum Dickkopf 1 Levels in Sclerostin Deficiency
journal, February 2014


Van Buchem disease: Clinical, biochemical, and densitometric features of patients and disease carriers
journal, March 2013


Inhibition of tumorigenesis driven by different Wnt proteins requires blockade of distinct ligand-binding regions by LRP6 antibodies
journal, August 2010


Sclerostin Inhibition Reverses Skeletal Fragility in an Lrp5-Deficient Mouse Model of OPPG Syndrome
journal, November 2013


HDAC5 Controls MEF2C-Driven Sclerostin Expression in Osteocytes: HDAC5 REGULATES SCLEROSTIN LEVELS IN OSTEOCYTES
journal, February 2015


Sost, independent of the non-coding enhancer ECR5, is required for bone mechanoadaptation
journal, November 2016


A Mutation in the LDL Receptor–Related Protein 5 Gene Results in the Autosomal Dominant High–Bone-Mass Trait
journal, January 2002


High-bone-mass-producing mutations in the Wnt signaling pathway result in distinct skeletal phenotypes
journal, November 2011


Standardized nomenclature, symbols, and units for bone histomorphometry: A 2012 update of the report of the ASBMR Histomorphometry Nomenclature Committee
journal, December 2012


Sclerostin antibody treatment enhances bone strength but does not prevent growth retardation in young mice treated with dexamethasone
journal, August 2011


The LRP5 High-Bone-Mass G171V Mutation Disrupts LRP5 Interaction with Mesd
journal, May 2004


Romosozumab in Postmenopausal Women with Low Bone Mineral Density
journal, January 2014


Sclerostin Deficiency Is Linked to Altered Bone Composition: SCLEROSTIN DEFICIENCY IS LINKED TO ALTERED BONE COMPOSITION
journal, September 2014


Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density, and bone strength
journal, January 2010


LDL Receptor-Related Protein 5 (LRP5) Affects Bone Accrual and Eye Development
journal, November 2001


High bone mass due to novel LRP5 and AMER1 mutations
journal, December 2017


Oropharyngeal Skeletal Disease Accompanying High Bone Mass and Novel LRP5 Mutation
journal, December 2004


Unique regulation of SOST, the sclerosteosis gene, by BMPs and steroid hormones in human osteoblasts
journal, August 2004


Modulation of Wnt signaling influences fracture repair: WNT MODULATION AND FRACTURE REPAIR
journal, January 2010


    Works referencing / citing this record:

    Transferrin receptor 2 controls bone mass and pathological bone formation via BMP and Wnt signalling
    journal, January 2019


    Wnt Antagonists in Hematopoietic and Immune Cell Fate: Implications for Osteoporosis Therapies
    journal, March 2019


    The Regulation of Bone Metabolism and Disorders by Wnt Signaling
    journal, November 2019


    Regulatory mechanisms of sclerostin expression during bone remodeling
    journal, October 2018


    MiR‐291a‐3p regulates the BMSCs differentiation via targeting DKK1 in dexamethasone‐induced osteoporosis
    journal, October 2019


    Overcoming natural Wnt inhibition to optimize therapy
    journal, January 2019


    Osteogenic Dkk1 Mediates Glucocorticoid‐Induced but Not Arthritis‐Induced Bone Loss
    journal, March 2019


    Antiresorptive and anabolic agents in the prevention and reversal of bone fragility
    journal, February 2019