The role of RAB12 in inhibiting osteogenic differentiation and driving metabolic dysregulation in osteoporosis.

AIMS

The osteogenic differentiation of mesenchymal stem cells (MSCs) is crucial in osteoporosis, and the metabolic level of the bone microenvironment directly affects metabolic dysregulation in postmenopausal women. RAB12 is a member of the small GTPase Rab family proteins, known to play an important role in autophagy. However, the role of RAB12 in the osteogenic differentiation of osteoporotic hMSCs remains unclear.

MATERIALS AND METHOD

Immunohistochemical staining was used to validate the high expression of RAB12 in aged osteoporotic mouse models and ovariectomized (OVX) mouse models. Co-immunoprecipitation (Co-IP) and LC-MS/MS were employed to explore downstream proteins that may interact with RAB12. Adenovirus containing RAB12 siRNA sequences was injected into the tail vein of OVX osteoporotic mice to analyze the impact of the RAB12/PCBP1/GLUT1 axis on MSC osteogenic differentiation.

KEY FINDINGS

We found that RAB12 expression is upregulated in elderly osteoporotic patients and in osteoporotic mouse models. RAB12 negatively regulates the osteogenic differentiation of hMSCs both in vivo and in vitro. RAB12 interacts with the PCBP1 protein, affecting its autophagic degradation when its expression levels change. RAB12 regulates the transcriptional level of GLUT1 by influencing the autophagic degradation of PCBP1, thereby affecting MSC's regulation of glucose uptake, which in turn impacts MSC osteogenic differentiation and metabolic changes.

SIGNIFICANCE

RAB12 negatively regulates osteogenic differentiation through the PCBP1/GLUT1 axis, affecting glucose metabolism levels in the bone microenvironment. RAB12 may serve as a potential target for the treatment of osteoporosis and postmenopausal metabolic dysregulation.