Abstract
As brain and bone disorders represent major health issues worldwide, substantial clinical investigations demonstrated a bidirectional crosstalk on several levels, mechanistically linking both apparently unrelated organs. While multiple stress, mood and neurodegenerative brain disorders are associated with osteoporosis, rare genetic skeletal diseases display impaired brain development and function. Along with brain and bone pathologies, particularly trauma events highlight the strong interaction of both organs. This review summarizes clinical and experimental observations reported for the crosstalk of brain and bone, followed by a detailed overview of their molecular bases. While brain-derived molecules affecting bone include central regulators, transmitters of the sympathetic, parasympathetic and sensory nervous system, bone-derived mediators altering brain function are released from bone cells and the bone marrow. Although the main pathways of the brain-bone crosstalk remain ‘efferent’, signaling from brain to bone, this review emphasizes the emergence of bone as a crucial ‘afferent’ regulator of cerebral development, function and pathophysiology. Therefore, unraveling the physiological and pathological bases of brain-bone interactions revealed promising pharmacologic targets and novel treatment strategies promoting concurrent brain and bone recovery.
Highlights
While the brain is regarded as the principal coordinator of body homeostasis by regulating organ activity and their crosstalk, bone features hematopoietic, endocrine metabolic and storage functions along with its predominant mechanical role
Multiple stress, mood and neurodegenerative brain pathologies were previously correlated with bone loss, while only a limited number of genetic skeletal diseases was associated with the modulation of brain development and function
- reduction of Bone mineral density (BMD) following traumatic brain injury (TBI) - TBI enhances the formation of heterotopic ossification (HO) - TBI with concomitant fracture showed an accelerated fracture healing and enlarged callus formation, potentially caused by: - dominance of neuronal mechanisms and neuroinflammation - calvaria anabolic response mediated by cannabinoid-1 receptor - leptin-deficiency eliminates positive effect - hippocampus and calcitonin gene-related peptide (CGRP) - SDF-1 promotes endochondral bone repair - elevated levels of leptin in CSF and growth hormone (GH)/insulin-like growth factor 1 (IGF-1) in serum - elevated serum arachidonic acid following TBI, which promotes the expression of BGLAP and osteoblasts proliferation - elevated serum Calcitonin gene-related peptide (CGRP) following TBI - elevated secretion of CGRP following TBI - close association of serum leptin and callus volume - release of osteogenic factors into the serum following TBI
Summary
While the brain is regarded as the principal coordinator of body homeostasis by regulating organ activity and their crosstalk, bone features hematopoietic, endocrine metabolic and storage functions along with its predominant mechanical role. Brain and bone seem apparently unrelated, exceptional clinical and experimental evidence propose a bilateral dependence of both organs [1,2]. We first recapitulate clinical observations and confirming experimental studies, demonstrating brain-bone interconnection. Thereafter, we provide a detailed overview of the molecular bases regarding these bilateral interactions. Based on this mechanistic understanding, we review promising therapeutic targets for disorders affecting brain and bone
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