Effects of novel raloxifene analogs alone or in combination with mechanical loading in the Col1a2G610c/+ murine model of osteogenesis imperfecta
Copyright © 2023 Elsevier Inc. All rights reserved..
Osteogenesis imperfecta (OI) is a hereditary bone disease in which gene mutations affect collagen formation, leading to a weak, brittle bone phenotype that can cause severe skeletal deformity and increased fracture risk. OI interventions typically repurpose osteoporosis medications to increase bone mass, but this approach does not address compromised tissue-level material properties. Raloxifene (RAL) is a mild anti-resorptive used to treat osteoporosis that has also been shown to increase bone strength by a-cellularly increasing bone bound water content, but RAL cannot be administered to children due to its hormonal activity. The goal of this study was to test a RAL analog with no estrogen receptor (ER) signaling but maintained ability to reduce fracture risk. The best performing analog from a previous analog characterization project, named RAL-ADM, was tested in an in vivo study. Female wildtype (WT) and Col1a2G610C/+ (G610C) mice were randomly assigned to treated or untreated groups, for a total of 4 groups (n = 15). Starting at 10 weeks of age, all mice underwent compressive tibial loading 3×/week to induce an anabolic bone formation response in conjunction with RAL-ADM treatment (0.5 mg/kg; 5×/week) for 6 weeks. Tibiae were scanned via microcomputed tomography then tested to failure in four-point bending. RAL-ADM had reduced ER affinity, and increased post-yield properties, but did not improve bone strength in OI animals, suggesting some properties can be improved by RAL analogs but further development is needed to create an analog with decidedly positive impacts to OI bone.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:179 |
|---|---|
| Enthalten in: |
Bone - 179(2024) vom: 04. Feb., Seite 116970 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Kohler, Rachel [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 07.01.2024 Date Revised 04.03.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.bone.2023.116970 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM364689536 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM364689536 | ||
| 003 | DE-627 | ||
| 005 | 20240305232039.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.bone.2023.116970 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1317.xml |
| 035 | |a (DE-627)NLM364689536 | ||
| 035 | |a (NLM)37977416 | ||
| 035 | |a (PII)S8756-3282(23)00303-4 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Kohler, Rachel |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Effects of novel raloxifene analogs alone or in combination with mechanical loading in the Col1a2G610c/+ murine model of osteogenesis imperfecta |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 07.01.2024 | ||
| 500 | |a Date Revised 04.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 Elsevier Inc. All rights reserved. | ||
| 520 | |a Osteogenesis imperfecta (OI) is a hereditary bone disease in which gene mutations affect collagen formation, leading to a weak, brittle bone phenotype that can cause severe skeletal deformity and increased fracture risk. OI interventions typically repurpose osteoporosis medications to increase bone mass, but this approach does not address compromised tissue-level material properties. Raloxifene (RAL) is a mild anti-resorptive used to treat osteoporosis that has also been shown to increase bone strength by a-cellularly increasing bone bound water content, but RAL cannot be administered to children due to its hormonal activity. The goal of this study was to test a RAL analog with no estrogen receptor (ER) signaling but maintained ability to reduce fracture risk. The best performing analog from a previous analog characterization project, named RAL-ADM, was tested in an in vivo study. Female wildtype (WT) and Col1a2G610C/+ (G610C) mice were randomly assigned to treated or untreated groups, for a total of 4 groups (n = 15). Starting at 10 weeks of age, all mice underwent compressive tibial loading 3×/week to induce an anabolic bone formation response in conjunction with RAL-ADM treatment (0.5 mg/kg; 5×/week) for 6 weeks. Tibiae were scanned via microcomputed tomography then tested to failure in four-point bending. RAL-ADM had reduced ER affinity, and increased post-yield properties, but did not improve bone strength in OI animals, suggesting some properties can be improved by RAL analogs but further development is needed to create an analog with decidedly positive impacts to OI bone | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a 4-pt bending mechanics | |
| 650 | 4 | |a Bone quality | |
| 650 | 4 | |a Combination treatment | |
| 650 | 4 | |a Selective estrogen receptor modulator | |
| 650 | 4 | |a Tibial loading | |
| 650 | 4 | |a micro-CT | |
| 650 | 7 | |a Raloxifene Hydrochloride |2 NLM | |
| 650 | 7 | |a 4F86W47BR6 |2 NLM | |
| 700 | 1 | |a Creecy, Amy |e verfasserin |4 aut | |
| 700 | 1 | |a Williams, David R |e verfasserin |4 aut | |
| 700 | 1 | |a Allen, Matthew R |e verfasserin |4 aut | |
| 700 | 1 | |a Wallace, Joseph M |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Bone |d 1992 |g 179(2024) vom: 04. Feb., Seite 116970 |w (DE-627)NLM01297238X |x 1873-2763 |7 nnns |
| 773 | 1 | 8 | |g volume:179 |g year:2024 |g day:04 |g month:02 |g pages:116970 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.bone.2023.116970 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 179 |j 2024 |b 04 |c 02 |h 116970 | ||