Mechanisms of aging-related secretory phenotype regulation in osteoporosis: Network regulation, trade-offs and homeostasis.

Abstract

Cellular senescence is defined as a stable state of cell cycle arrest, characterized by the loss of proliferative capacity. This process can be triggered by diverse intracellular and extracellular stimuli. Senescent cells exhibit multiple hallmark features, including upregulation of cell cycle inhibitory proteins p16INK4a and p21Cip1, activation of DNA damage response, alterations in cellular architecture, and metabolic reprogramming. A prominent characteristic of senescent cells is their ability to secrete a heterogeneous array of bioactive molecules, collectively termed the senescence-associated secretory phenotype (SASP). These SASP components encompass cytokines, chemokines, growth factors, proteases, and other signaling mediators that exert biological functions through autocrine and paracrine mechanisms.With global population aging, osteoporosis has emerged as a critical public health challenge worldwide. Emerging evidence underscores the close association between osteoporosis and cellular senescence. During aging, the accumulation of senescent cells leads to enhanced SASP production, which contains pro-inflammatory cytokines, chemokines, and other mediators. These SASP factors not only propagate the senescence phenotype but also disrupt bone homeostasis by impairing the functionality of bone tissue cells, thereby accelerating skeletal aging. Recent advances highlight SASP as a promising therapeutic target for bone metabolic disorders such as osteoporosis. However, the precise molecular mechanisms through which SASP regulates bone cell populations remain incompletely elucidated.Addressing this knowledge gap, the present study aims to investigate the regulatory mechanisms of SASP in bone tissue cells, with the ultimate goal of providing mechanistic insights for developing novel strategies against age-related bone metabolic diseases.