The Effects of Calcitonin Gene-Related Peptide on Bone Homeostasis and Regeneration

The goals of this review are two folds: (1) to describe the recent understandings on the roles of calcitonin gene-related peptide-α (CGRP) in bone homeostasis and the underlying mechanisms of related neuronal regulation and (2) to propose innovative CGRP-modulated approaches for enhancing bone regeneration in challenging bone disorders.

CGRP is predominantly produced by the densely distributed sensory neuronal fibers in bone, declining with age. Under mechanical and biochemical stimulations, CGRP releases and exerts either physiological or pathophysiological roles. CGRP at physiological level orchestrates the communications of bone cells with cells of other lineages, affecting not only osteogenesis, osteoclastogenesis, and adipogenesis but also angiogenesis, demonstrating with pronounced anabolic effect, thus is essential for maintaining bone homeostasis, with tuned nerve-vessel-bone network. In addition, its effects on immunity and cell recruitment are also crucial for bone fracture healing. Binding to the G protein-coupled receptor composited by calcitonin receptor-like receptor (CRLR) and receptor activity modifying protein 1 (RAMP1) on cellular surface, CGRP triggers various intracellular signaling cascades involving cyclic adenosine monophosphate (cAMP) and cAMP response element-binding protein (CREB). Peaking at early stage post-fracture, CGRP promotes bone formation, displaying with larger callus. Then CGRP gradually decreases over time, allowing normal or physiological bone remodeling. By elevating CGRP at early stage, low-intensity pulsed ultrasound (LIPUS), electrical stimulation, and magnesium-based bio-mineral products may promisingly accelerate bone regeneration experimentally in medical conditions like osteoporosis, osteoporotic fracture, and spine fusion. Excess CGRP expression is commonly observed in pathological conditions including cancer metastatic lesions in bone and fracture delayed- or non-healing, resulting in persistent chronic pain. To date, these discoveries have largely been limited to animal models. Clinical applications are highly desirable. Compelling evidence show the anabolic effects of CGRP on bone in animals. However, further validation on the role of CGRP and the underlying mechanisms in human skeletons is required. It remains unclear if it is type H vessel connecting neuronal CGRP to osteogenesis, and if there is only specific rather than all osteoprogenitors responsible to CGRP. Clear priority should be put to eliminate these knowledge gaps by integrating with high-resolution 3D imaging of transparent bulk bone and single-cell RNA-sequencing. Last but not the least, given that small molecule antagonists such as BIBN4096BS can block the beneficial effects of CGRP on bone, concerns on the potential side effects of humanized CGRP-neutralizing antibodies when systemically administrated to treat migraine in clinics are arising.