A neuroskeletal atlas of the mouse limb

ABSTRACT Nerves in bone play well-established roles in pain and vasoregulation and have been associated with progression of skeletal disorders including osteoporosis, fracture, arthritis and tumor metastasis. However, isolation of the region-specific mechanisms underlying these relationships is limited by our lack of comprehensive maps of skeletal innervation. To overcome this, we mapped sympathetic adrenergic and sensory peptidergic axons within the limb in two strains of mice (B6 and C3H). In the periosteum, these maps were related to the surrounding musculature, including entheses and myotendinous attachments to bone. Locally, three distinct patterns of innervation (Type I, II, III) were defined within established sites that are important for bone pain, bone repair, and skeletal homeostasis. In addition, we mapped the major nerve branches and areas of specialized mechanoreceptors. This work is intended to serve as a guide during the design, implementation, and interpretation of future neuroskeletal studies and was compiled as a resource for the field as part of the NIH SPARC consortium.