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Gorab deficiency in skin dermis accelerates aging and is associated with dysregulation of RCHY1-mediated P53
Yanhong Li1, Wei Liang1, Yanfeng Xu1
1NHC Key Laboratory of Comparative Medicine, National Human Diseases Animal Model Resource Center, National Center of Technology Innovation for Animal Model; Key Laboratory of Pathogen Infection Prevention and Control (Peking Union Medical College), Ministry of Education, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Background:
Mutations in and functional inactivation of the Gorab gene cause gerodermia osteodysplastica (GO), a disease featuring wrinkled skin and osteoporosis, but the underlying mechanisms of skin aging remain incompletely understood.
Methods:
By crossing the Gorab conditional knockout mouse model (Gorabflox/flox) with Col1a2-cre/ERT tool mice, pregnant dams at embryonic day 16.5 (E16.5d) and 6-week-old offspring were induced with tamoxifen dissolved in a corn oil solution (3 mg/150 μL per mouse) to develop a dermal Gorab knockout mouse model. Then, aging phenotypes were analyzed, and mechanistic studies were performed.
Results:
Conditional knockout of Gorab at two different time points (embryonic and postnatal) resulted in elevated levels of aging-related proteins (P53, P21, P16) and a reduction in levels of extracellular matrix (ECM) components, including collagen, fibrillin-1, vimentin, fibronectin, laminin, and versican in the ventral and dorsal skin of adult mice. Postnatal knockout had a relatively more pronounced effect on skin aging-related changes. Mechanistically, Gorab knockout impaired the ubiquitination and promoted the accumulation of P53 protein, likely through regulating the E3 ligase RCHY1. This was accompanied by increased HDAC2 levels, reduced histone acetylation, and consequent downregulation of skin ECM proteins, outlining a potential pathway for accelerated skin aging.
Conclusions:
This study elucidates that Gorab mutations in the dermis promote skin aging by causing P53 accumulation and disrupting ECM expression via epigenetic regulation. These findings clarify the biological role of Gorab in skin aging and provide a theoretical basis for related mechanistic research and potential preventive strategies.
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