Endocrinology of bone/brain crosstalk

Abstract

Bone metabolism is regulated by the action of two skeletal cells: osteoblasts and osteoclasts. This process is controlled by many genetic, hormonal and lifestyle factors, but today more and more studies have allowed us to identify a neuronal regulation system termed ‘bone–brain crosstalk’, which highlights a direct relationship between bone tissue and the nervous system. The first documentation of an anatomic relationship between nerves and bone was made via a wood cut by Charles Estienne in Paris in 1545. His diagram demonstrated nerves entering and leaving the bones of a skeleton. Later, several studies were conducted on bone innervation and, as of today, many observations on the regulation of bone remodeling by neurons and neuropeptides that reside in the CNS have created a new research field, that is, neuroskeletal research.

Keywords:

• 5-OH-tryptamine
• adrenocorticotropin
• animal and human studies
• β-adrenergic system
• bone remodeling
• brain–derived neurotrophic factor
• cannabinoids
• CNS
• depression
• leptin
• neuropeptides
• osteoporosis disease
• sympathetic nervous system

Financial & competing interests disclosure

This work was supported by F.I.R.M.O. Fondazione Raffaella Becagli to MLB. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Bone remodeling is a process regulated by several different signals whose targets can be bone cells (osteoclasts and osteoblasts at various stages of their lifespan), which ensures the maintenance of bone mass and microarchitecture, and contributes to mineral body homeostasis.

• Clues about the existence of neuronal and central regulatory components of the bone remodeling process have been reported in clinical literature for several decades. To date, a key role of the hypothalamus has been shown through mediators such as leptin, serotonin, neuromedin U, cocaine and amphetamine-regulated transcript, neuropeptide Y, cannabinoids, the β-adrenergic system and a number of neuropeptides including glutamate, calcitonin gene-related protein, substance P and vasoactive intestinal peptide. The hypothalamus appears to be involved in the processes of bone remodeling by the following factors: brain-derived neurotrophic factor, growth hormone and gonadotropin-releasing hormone.

• Several human diseases represent an important connection point between the nervous and skeletal system. From a biochemical point of view, there are several scientific evidences demonstrating the relationship between depression and osteoporosis. The depression reduces the bone mineral density through activation of the hypothalamic–pituitary–adrenal system, and through the activation of processes of neuroinflammation with production of proinflammatory cytokines (IL-6, IL-1, TNF-α).

• The osteoporotic fracture determines an organism’s response to stress with activation of the hypothalamic–pituitary–adrenal axis, which acts on the CNS by influencing the levels of monoamines, neurotrophic factors and modulating the inflammatory response and activation of inflammatory signals in the CNS (e.g., NF-κB) causing neurotoxicity and reduced neuroplasticity (reduced brain-derived neurotrophic factor) with symptoms of depression and cognitive impairment.

• Future research will be mainly directed to the discovery of new therapeutic targets for bone and nervous diseases.