Bone-to-Brain: A Round Trip in the Adaptation to Mechanical Stimuli

Abstract

Besides the classical ones (support/protection, hematopoiesis, storage for calcium, and phosphate) multiple roles emerged for bone tissue, definitively making it an organ. Particularly, the endocrine function, and in more general terms, the capability to sense and integrate different stimuli and to send signals to other tissues, has highlighted the importance of bone in homeostasis. Bone is highly innervated and hosts all nervous system branches; bone cells are sensitive to most of neurotransmitters, neuropeptides, and neurohormones that directly affect their metabolic activity and sensitivity to mechanical stimuli. Indeed, bone is the principal mechanosensitive organ. Thanks to the mechanosensing resident cells, and particularly osteocytes, mechanical stimulation induces metabolic responses in bone forming (osteoblasts) and bone resorbing (osteoclasts) cells that allow the adaptation of the affected bony segment to the changing environment. Once stimulated, bone cells express and secrete, or liberate from the entrapping matrix, several mediators (osteokines) that induce responses on distant targets. Brain is a target of some of these mediator [e.g., osteocalcin, lipocalin2, sclerostin, Dickkopf-related protein 1 (Dkk1), and fibroblast growth factor 23], as most of them can cross the blood-brain barrier. For others, a role in brain has been hypothesized, but not yet demonstrated. As exercise effectively modifies the release and the circulating levels of these osteokines, it has been hypothesized that some of the beneficial effects of exercise on brain functions may be associated to such a bone-to-brain communication. This hypothesis hides an interesting clinical clue: may well-addressed physical activities support the treatment of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases?

Acute Effects of Strength and Endurance Training on Bone Turnover Markers in Young Adults and Elderly Men

“…We speculate that the high load and rapid execution (i.e., high rate of force development) in our ST model could be the decisive factor regarding the sclerostin response, as this type of execution is more similar to plyometric exercise. Still, sclerostin’s response to exercise is not yet clear and requires further research, as conflicting reports exist regarding circulating sclerostin alterations, from elevation, no effect, and suppression ( 55 ).…”

Sclerostin influences exercise-induced adaptations in body composition and white adipose tissue morphology in male mice

“…iWAT controls peripheral tissue homeostasis through the storage and timely release of substrates that contributes to energy expenditure in peripheral tissues (e.g., liver, and skeletal muscle) [21, 50, 51]. However, the discrepancy in energy expenditure and carbohydrate and fat oxidation between sclerostin and saline injected mice suggests other metabolically active tissues, like bone [52, 53], brain [54], liver [18, 55], and skeletal muscle [56] may be either directly (i.e., sclerostin binding and influencing cell differentiation and metabolism) or indirectly (i.e., influence on lipolysis in iWAT) contributing to these changes in metabolism. While we found no effect of EXT or sclerostin injection on activation of lipolytic enzymes, it may be because we measured basal levels and not their activation in response to physiological stimuli (e.g., adrenergic activation) that could reveal functional differences.…”

Rethinking Fragility Fractures in Type 2 Diabetes: The Link between Hyperinsulinaemia and Osteofragilitas

“…This leads to the metabolic healthy phenotype of higher levels of OCN synthesis and carboxylation capacity, resulting in fracture-resistant bone, with osteocytes maintaining basal bone remodelling. Furthermore, the resultant ability to endogenously produce OCN, enables bone to participate in its endocrine-action on other tissues and organs, further contributing to improved glucose homeostasis and insulin sensitivity [109]. Restriction of dietary carbohydrate intake simultaneously maintains low glucose levels and minimises additional exogenous stimulus on insulin secretion, thus maintaining both markers in the low healthy physiological range.…”

“…This area of research is in its infancy and warrants further investigation, given the increase in cognitive decline, Alzheimer's disease (AD) and Parkinson's disease (PD) that are increasingly recognised as conditions of hyperinsulinaemia and mitochondrial distress [153][154][155]. Increasing evidence is demonstrating a role of OCN in neurological health and disease [109,156,157]. This leads to further concerns with the increasing earlier rates of obesity, T2D and hyperinsulinaemia in women.…”