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bioRxiv · 10.64898/2025.12.14.691656

Melanoregulin deficiency affects bone maintenance and lean body mass

Musskopf, M. L.·Goncalves, V. D. P.·Tuin, S.·Wong, S.-W.·Boesze-Battaglia, K.·Miguez, P. A.
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Abstract

ObjectivesStudies 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 Mregdsu/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. MethodsMice 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. ResultsThere 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. ConclusionsMREG 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 MREGs 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.

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Musskopf, M. L., Goncalves, V. D. P., Tuin, S., Wong, S.-W., Boesze-Battaglia, K., Miguez, P. A.. 2025-12-16. Melanoregulin deficiency affects bone maintenance and lean body mass. https://doi.org/10.64898/2025.12.14.691656

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