Ontogeny of sensory and autonomic nerves in the developing mouse skeleton

Nerves in Bone: Evolving Concepts in Pain and Anabolism

“…At the site of endochondral ossification, de Castro detected nerve fibers terminating near osteoblasts that atrophied upon calcification, suggesting a precise spatial and temporal influence of nerves in skeletal development (referenced in Sherman). In the mouse and rat, neurons appear first in the perichondrium of the diaphysis almost simultaneous with the first signs of mineralization . Nerves accompanying blood vessels invade through the cartilage canals to reach the primary, and later the secondary, ossification centers, where they maintain a close relationship to the bone‐cartilage interface and the endosteum, sites of high osteogenic activity.…”

“…In the mouse and rat, neurons appear first in the perichondrium of the diaphysis almost simultaneous with the first signs of mineralization. (29,42,50,63) Nerves accompanying blood vessels invade through the cartilage canals to reach the primary, and later the secondary, ossification centers, where they maintain a close relationship to the bone-cartilage interface and the endosteum, sites of high osteogenic activity. At each site of bone formation, the appearance of sensory nerve fibers coincides with vascularization and ossification, and precedes the appearance of sympathetic nerve fibers, (50,63) hinting at a predominant role of the sensory nervous system in bone development.…”

“…(29,42,50,63) Nerves accompanying blood vessels invade through the cartilage canals to reach the primary, and later the secondary, ossification centers, where they maintain a close relationship to the bone-cartilage interface and the endosteum, sites of high osteogenic activity. At each site of bone formation, the appearance of sensory nerve fibers coincides with vascularization and ossification, and precedes the appearance of sympathetic nerve fibers, (50,63) hinting at a predominant role of the sensory nervous system in bone development. Ablation of sensory innervation by genetic or pharmacological approaches does not inhibit bone development, but consistently results in decreased bone mass in adult mice, (47,64,65) suggesting that sensory nerves contribute to skeletal homeostasis and mineralization during development.…”

Sensory neurons sprouting is dependent on osteoclast-derived extracellular vesicles involving the activation of epidermal growth factor receptors

“…Different studies point to a parallel between osteoclast activity and sensory neurons outgrowth in physiological and pathological conditions (Cheung et al, 2009; Clarke, 2008; Gajda et al, 2005; Kumar et al, 2011; Mediati et al, 2014; Nagae et al, 2006; Ni et al, 2019; Reddy et al, 1999; Riminucci et al, 2003; Sisask et al, 1996, 2013; Zhu et al, 2019). Several reports have described that during embryonic long bone development, osteoclasts are found in the process of endochondral ossification, degrading the newly formed trabecular bone, creating the bone marrow space (Clarke, 2008).…”

“…Nerve fibers present in the bone microenvironment have been directly implicated in bone homeostasis and regeneration (Chenu, 2004; Chenu and Marenzana, 2005; Elefteriou, 2008; Elefteriou et al, 2014; Patel and Elefteriou, 2007). Anatomical mapping of innervation during skeletal development shows co-localization of nerve fibers with a rich capillary network in areas with high osteogenic activity (Gomez et al, 2005; Hukkanen et al, 1993; Li et al, 2007; Sisask et al, 2013; Tomlinson et al, 2016) and the pattern of neuronal dynamics observed during bone development is typically repeated (Hukkanen et al, 1993; Li et al, 2001; Madsen et al, 1998; Nordsletten et al, 1994), highlighting the critical role of neuronal regulation. Several denervation studies have revealed an impairment on fracture healing, emphasizing the impact of the peripheral nervous system on bone turnover (Bove et al, 2009; Cherruau et al, 1999; Edoff et al, 1997; Hill and Elde, 1991; Song et al, 2012).…”