Osteocytes in bone aging: Advances, challenges, and future perspectives

Osteocytes play a critical role in maintaining bone homeostasis and in regulating skeletal response to hormones and mechanical loading. Substantial evidence have demonstrated that osteocytes and their lacunae exhibit morphological changes in aged bone, indicating the underlying involvement of osteocytes in bone aging. Notably, recent studies have deciphered aged osteocytes to have characteristics such as impaired mechanosensitivity, accumulated cellular senescence, dysfunctional perilacunar/canalicular remodeling, and degenerated lacuna-canalicular network. However, detailed molecular mechanisms of osteocytes remain unclear. Nonetheless, osteocyte transcriptomes analyzed via advanced RNA sequencing (RNA-seq) techniques have identified several bone aging-related genes and signaling pathways, such as Wnt, Bmp/TGF, and Jak-STAT. Moreover, inflammation, immune dysfunction, energy shortage, and impaired hormone responses possibly affect osteocytes in age-related bone deterioration. In this review, we summarize the hallmarks of aging bone and osteocytes and discuss osteocytic mechanisms in age-related bone loss and impaired bone quality. Furthermore, we provide insights into the challenges faced and their possible solutions when investigating osteocyte transcriptomes. We also highlight that single-cell RNA-seq can decode transcriptomic messages in aged osteocytes; therefore, this technique can promote novel single cell-based investigations in osteocytes once a well-established standardized protocol specific for osteocytes is developed. Interestingly, improved understanding of osteocytic mechanisms have helped identify promising targets and effective therapies for aging-related osteoporosis and fragile fractures.