CLSPN actives Wnt/ß-catenin signaling to facilitate glycolysis and cell proliferation in oral squamous cell carcinoma.

OBJECTIVE: Oral squamous cell carcinoma (OSCC) is a common malignancy with a poor prognosis. This study aimed to determine the influence and underlying mechanisms of CLSPN on OSCC. METHODS: CLSPN expression was tested using quantitative real-time polymerase chain reaction, immunohistochemistry, and western blotting. Flow cytometry, cell counting kit, and colony formation assays were performed to determine OSCC cell apoptosis, viability, and proliferation, respectively. In OSCC cells, the extracellular acidification rate (ECAR), oxygen consumption rate (OCR), glucose uptake, and lactate production were determined using the corresponding kits. Changes in the protein levels of HK2, PKM2, LDHA, Wnt3a, and ß-catenin were assessed using western blotting. RESULTS: CLSPN expression was increased in OSCC tissues. Overexpression of CLSPN in HSC-2 cells promoted cell proliferation, increased the levels of ECAR, glucose uptake, and lactate production, and increased the protein levels of HK2, PKM2, LDHA, Wnt3a, and ß-catenin, but inhibited OCR levels and apoptosis. The knockdown of CLSPN in CAL27 cells resulted in the opposite results. Moreover, the effects of CLSPN overexpression on glycolysis and OSCC cell proliferation were reversed by Wnt3a knockdown. In vivo, knockdown of CLSPN restrained tumor growth, glycolysis, and the activation of Wnt/ß-catenin signaling. CONCLUSION: CLSPN promoted glycolysis and OSCC cell proliferation, and reduced apoptosis, which was achieved by the activation of Wnt/ß-catenin signaling pathway.

Emerging roles of nerve-bone axis in modulating skeletal system.

Over the past decades, emerging evidence in the literature has demonstrated that the innervation of bone is a crucial modulator for skeletal physiology and pathophysiology. The nerve-bone axis sparked extensive preclinical and clinical investigations aimed at elucidating the contribution of nerve-bone crosstalks to skeleton metabolism, homeostasis, and injury repair through the perspective of skeletal neurobiology. To date, peripheral nerves have been widely reported to mediate bone growth and development and fracture healing via the secretion of neurotransmitters, neuropeptides, axon guidance factors, and neurotrophins. Relevant studies have further identified several critical neural pathways that stimulate profound alterations in bone cell biology, revealing a complex interplay between the skeleton and nerve systems. In addition, inspired by nerve-bone crosstalk, novel drug delivery systems and bioactive materials have been developed to emulate and facilitate the process of natural bone repair through neuromodulation, eventually boosting osteogenesis for ideal skeletal tissue regeneration. Overall, this work aims to review the novel research findings that contribute to deepening the current understanding of the nerve-bone axis, bringing forth some schemas that can be translated into the clinical scenario to highlight the critical roles of neuromodulation in the skeletal system.

The Potential Role and Therapeutic Relevance of Cellular Senescence in Skeletal Pathophysiology.

Biological aging profoundly impairs the homeostasis of the skeletal system. Cellular senescence, a hallmark of biological aging, plays an instrumental role in bone disease. The underlying mechanisms of cellular senescence, triggered by both intracellular and extracellular stimuli, are multifaceted and yet to be uncovered. Recent research indicates that acute cellular senescence often serves beneficial roles, such as contributing to growth, development, and tissue regeneration. By contrast, chronic cellular senescence, primarily driven by the accumulation of senescent cells (SnCs) and the release of senescence-associated secretory phenotypes (SASP), has detrimental effects on the skeletal system by irreversibly disrupting bone homeostasis and promoting age-related disorders. Furthermore, the bone marrow is rich in immune cells and their exposure to SASP often leads to immune dysfunction, resulting in unresolved chronic inflammation and compromised adaptive immunity. Until now, the impact of SnCs and SASP on the skeleton has remained elusive. Meanwhile, extensive efforts are being made to combat age-related diseases through various strategies. Among them, SnCs and SASP are the primary targets for antiaging therapeutic clearance, resulting in the development of "senolytics" and "senomorphics," respectively. In this review, we summarize and highlight the role of SnCs and SASP in skeletal pathophysiology, the mechanism of cellular senescence in affecting bone metabolism, and potential therapeutic approaches, particularly senolytics and senomorphics, in treating cellular senescence-related bone diseases.