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Melanoregulin Deficiency Affects Bone Maintenance and Lean Body Mass
M L Musskopf1, V De P Gonçalves2, S Tuin3
1Department of Restorative Sciences, Adams School of Dentistry, UNC-CH, Chapel Hill, NC, USA.
Objectives:
Studies documented the association of melanoregulin (MREG), a cargo-sorting protein, with its binding partner, the autophagic protein, microtubule-associated protein 1 light chain 3B (LC3B) in macrophages which could affect bone physiology due to the importance of autophagy in osteoclast function. Herein we propose to test the hypothesis that MREG modulates bone remodeling. Therefore, we analyzed the Mreg dsu/dsu mutant mice for bone mass, growth plate microarchitecture, and bone marrow-derived osteoclast function to understand how lack of MREG affects bone and mass at two different time points.
Methods:
Mice femurs from wild type and MREG-/- male mice (on C57BL6)/J background) were harvested at 4 and 10 months and imaged by microcomputed tomography to assess bone mass parameters. Femurs were processed for histology by H&E and TRAP staining for assessment of osteoclast numbers. Primary bone marrow-derived macrophages from 3-week-old mice were harvested to assess osteoclast differentiation and function via TRAP, resorptive assay and Western Blot for osteoclast differentiation markers. In addition, a separate cohort of mice were analyzed via EchoMRI to characterize total lean vs. fat whole body mass.
Results:
There was a statistically significant difference in bone volume of 10-month old mice in wild type vs. MREG-/- with MREG mutation suggesting a preservative effect on phenotypical bone parameters as the mice age. A reduction in adipose tissue but an increase in osteoclast numbers was found histologically in MREG mutant femurs. Bone marrow-derived cells, however, showed reduced osteoclastic function in MREG-/-. The mutant mice presented a total lean mass significantly increased compared to wild type per EchoMRI.
Conclusions:
MREG deficiency seems to impact osteoclast numbers in vivo but not in vitro, although in vitro function was reduced. MREG deficiency favors lean mass preservation over fat accumulation in bones and body composition as mice age. This study provides the foundation for a more in-depth investigation of MREG's role in bone and systemic metabolism. It is possible that MREG can be a future target for new therapeutic modalities in inflammatory and metabolic bone diseases.
Insights
Melanoregulin (MREG) deficiency impacts bone remodeling and body composition in mice. MREG mutation preserves bone mass and increases lean mass, suggesting therapeutic potential for bone diseases.
Area of Science:
- Bone Biology and Metabolism
- Cellular Autophagy
- Macrophage Function
Background:
- Melanoregulin (MREG) is a cargo-sorting protein associated with the autophagic protein LC3B in macrophages.
- Autophagy plays a critical role in osteoclast function and bone remodeling.
- The specific role of MREG in bone physiology remains largely unexplored.
Purpose of the Study:
- To investigate the hypothesis that MREG modulates bone remodeling.
- To analyze the effects of MREG deficiency on bone mass, growth plate microarchitecture, and osteoclast function.
- To understand the impact of MREG absence on bone and body mass over time.
Main Methods:
- Microcomputed tomography (micro-CT) analysis of femurs from wild type and MREG knockout mice at 4 and 10 months.
- Histological assessment of femurs using H&E and TRAP staining for osteoclast enumeration.
- In vitro studies using bone marrow-derived macrophages to evaluate osteoclast differentiation and function.
- Whole-body composition analysis using EchoMRI to assess lean and fat mass.
Main Results:
- MREG deficiency showed a statistically significant preservation of bone volume in 10-month-old mice.
- Histological analysis revealed increased osteoclast numbers but reduced adipose tissue in MREG mutant femurs.
- In vitro assays demonstrated reduced osteoclastic function in MREG-deficient cells, despite increased osteoclast numbers in vivo.
- EchoMRI indicated a significant increase in total lean mass in MREG mutant mice compared to wild type.
Conclusions:
- MREG deficiency affects osteoclast numbers in vivo and impairs osteoclast function in vitro.
- MREG deficiency promotes lean mass preservation and reduces fat accumulation with aging.
- MREG's role in bone and systemic metabolism warrants further investigation for potential therapeutic applications in bone diseases.
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