PMID- 29844946
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20201001
IS  - 2095-4700 (Print)
IS  - 2095-6231 (Electronic)
IS  - 2095-4700 (Linking)
VI  - 6
DP  - 2018
TI  - Bone loss from Wnt inhibition mitigated by concurrent alendronate therapy.
PG  - 17
LID - 10.1038/s41413-018-0017-8 [doi]
LID - 17
AB  - Dysregulated Wnt signaling is associated with the pathogenesis of cancers, 
      fibrosis, and vascular diseases. Inhibition of Wnt signaling has shown efficacy 
      in various pre-clinical models of these disorders. One of the key challenges in 
      developing targeted anti-cancer drugs is to balance efficacy with on-target 
      toxicity. Given the crucial role Wnts play in the differentiation of osteoblasts 
      and osteoclasts, acute inhibition of Wnt signaling is likely to affect bone 
      homeostasis. In this study, we evaluated the skeletal effect of small molecule 
      inhibitor of an o-acyl transferase porcupine (PORCN) that prevents Wnt signaling 
      by blocking the secretion of all Wnts. Micro-computed tomography and 
      histomorphometric evaluation revealed that the bones of mice treated with two 
      structurally distinct PORCN inhibitors LGK974 and ETC-1922159 (ETC-159) had 
      loss-of-bone volume and density within 4 weeks of exposure. This decreased bone 
      mass was associated with a significant increase in adipocytes within the bone 
      marrow. Notably, simultaneous administration of a clinically approved 
      anti-resorptive, alendronate, a member of the bisphosphonate family, mitigated 
      loss-of-bone mass seen upon ETC-159 treatment by regulating activity of 
      osteoclasts and blocking accumulation of bone marrow adipocytes. Our results 
      support the addition of bone protective agents when treating patients with PORCN 
      inhibitors. Mitigation of bone toxicity can extend the therapeutic utility of Wnt 
      pathway inhibitors.
FAU - Madan, Babita
AU  - Madan B
AD  - 1Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, 
      169857 Singapore. ISNI: 0000 0004 0385 0924. GRID: grid.428397.3
FAU - McDonald, Mitchell J
AU  - McDonald MJ
AD  - 2Center for Cancer and Cell Biology and Program for Skeletal Disease and Tumor 
      Microenvironment, Van Andel Research Institute, Grand Rapids, MI 49503 USA. ISNI: 
      0000 0004 0406 2057. GRID: grid.251017.0
FAU - Foxa, Gabrielle E
AU  - Foxa GE
AD  - 2Center for Cancer and Cell Biology and Program for Skeletal Disease and Tumor 
      Microenvironment, Van Andel Research Institute, Grand Rapids, MI 49503 USA. ISNI: 
      0000 0004 0406 2057. GRID: grid.251017.0
FAU - Diegel, Cassandra R
AU  - Diegel CR
AD  - 2Center for Cancer and Cell Biology and Program for Skeletal Disease and Tumor 
      Microenvironment, Van Andel Research Institute, Grand Rapids, MI 49503 USA. ISNI: 
      0000 0004 0406 2057. GRID: grid.251017.0
FAU - Williams, Bart O
AU  - Williams BO
AD  - 2Center for Cancer and Cell Biology and Program for Skeletal Disease and Tumor 
      Microenvironment, Van Andel Research Institute, Grand Rapids, MI 49503 USA. ISNI: 
      0000 0004 0406 2057. GRID: grid.251017.0
FAU - Virshup, David M
AU  - Virshup DM
AUID- ORCID: 0000-0001-6976-850X
AD  - 1Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, 
      169857 Singapore. ISNI: 0000 0004 0385 0924. GRID: grid.428397.3
AD  - 3Department of Pediatrics, Duke University, Durham, NC USA. ISNI: 0000 0004 1936 
      7961. GRID: grid.26009.3d
LA  - eng
GR  - R01 AR053293/AR/NIAMS NIH HHS/United States
PT  - Journal Article
DEP - 20180525
PL  - China
TA  - Bone Res
JT  - Bone research
JID - 101608652
PMC - PMC5968037
COIS- B.M. and D.M.V. are co-inventors of a small molecule PORCN inhibitor.
EDAT- 2018/05/31 06:00
MHDA- 2018/05/31 06:01
PMCR- 2018/05/25
CRDT- 2018/05/31 06:00
PHST- 2017/09/30 00:00 [received]
PHST- 2018/02/01 00:00 [revised]
PHST- 2018/03/26 00:00 [accepted]
PHST- 2018/05/31 06:00 [entrez]
PHST- 2018/05/31 06:00 [pubmed]
PHST- 2018/05/31 06:01 [medline]
PHST- 2018/05/25 00:00 [pmc-release]
AID - 17 [pii]
AID - 10.1038/s41413-018-0017-8 [doi]
PST - epublish
SO  - Bone Res. 2018 May 25;6:17. doi: 10.1038/s41413-018-0017-8. eCollection 2018.