Activation of 4-1BB signaling in bone marrow stromal cells triggers bone loss via the p-38 MAPK-DKK1 axis in aged mice

Senile osteoporosis can cause bone fragility and increased fracture risks and has been one of the most prevalent and severe diseases affecting the elderly population. Bone formation depends on the proper osteogenic differentiation of bone marrow stromal cells (BMSCs) in the bone marrow microenvironment, which is generated by the functional relationship among different cell types in the bone marrow. With aging, bone marrow provides signals that repress osteogenesis. Finding the signals that oppose BMSC osteogenic differentiation from the bone marrow microenvironment and identifying the abnormal changes in BMSCs with aging are key to elucidating the mechanisms of senile osteoporosis. In a pilot experiment, we found that 4-1BBL and 4-1BB were more abundant in bone marrow from aged (18-month-old) mice than young (6-month-old) mice. Meanwhile, significant bone loss was observed in aged mice compared with young mice. However, very little data have been generated regarding whether high-level 4-1BB/4-1BBL in bone marrow was associated with bone loss in aged mice. In the current study, we found upregulation of 4-1BB in the BMSCs of aged mice, which resulted in the attenuation of the osteogenic differentiation potential of BMSCs from aged mice via the p38 MAPK-Dkk1 pathway. More importantly, bone loss of aged mice could be rescued through the blockade of 4-1BB signaling in vivo. Our study will benefit not only our understanding of the pathogenesis of age-related trabecular bone loss but also the search for new targets to treat senile osteoporosis. Bone formation: An off-switch for age-related osteoporosis A signaling pathway that suppresses the production of bone-forming cells with increasing age could offer a useful target for the treatment of osteoporosis. Bone is replenished by osteoblasts, cells that originate from reservoirs of bone marrow stromal cells (BMSCs). In age-related osteoporosis, suppressive signals inhibit the formation of new osteoblasts. Researchers led by Huoniu Ouyang of Shanghai Ninth People's Hospital and Liming Cheng at Tongji Hospital in China have identified an important component of this inhibition. They discovered that a signaling protein called 4-1BB is expressed at higher levels in BMSCs from aged mice than in those from young mice. Activation of this protein switches off osteoblast production and contributes to bone loss. Treatments that interfere with 4-1BB counter this degenerative process, suggesting a possible approach for therapeutic intervention.

Automated summary

Senile osteoporosis, affecting the elderly population, is caused by abnormal changes in bone marrow stromal cells and signaling pathways in the bone marrow microenvironment. Elevated levels of 4-1BB in aged mice inhibit osteogenic differentiation, leading to bone loss, which can be rescued by blocking the 4-1BB signaling pathway. These findings suggest a potential therapeutic target for age-related trabecular bone loss.