Fracture repair requires TrkA signaling by skeletal sensory nerves

Zhu, Li; Meyers, Carolyn A.; Chang, Leslie; Lee, Seungyong; Li, Zhi; Tomlinson, Ryan E.; Höke, Ahmet; Clemens, Thomas L.; James, Aaron W.

doi:10.1172/jci128428

Cited by 147 publications

(233 citation statements)

References 61 publications

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“…Furthermore, consistent with the wide-spread expression of NGF observed in fracture ( 25 , 26 ), anti-NGF antibodies decrease fracture-related pain behavior in mice ( 27 , 28 ). Subsequent research suggested that analgesia using anti-NGF antibodies can be achieved without affecting fracture healing outcomes ( 29 ), although others have shown that silencing the activation of TrkA diminishes innervation and stress fracture healing in mice ( 30 ). This concept of NGF acting as an osteoanabolic agent is consistent with earlier work, which reported that topical application of NGF to rib fractures decreased healing time in rats ( 27 ) and improved healing outcomes in distraction osteogenesis in rabbits ( 28 ).…”

Section: Skeletal Innervationmentioning

confidence: 99%

The Role of Nerves in Skeletal Development, Adaptation, and Aging

et al. 2020

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The skeleton is well-innervated, but only recently have the functions of this complex network in bone started to become known. Although our knowledge of skeletal sensory and sympathetic innervation is incomplete, including the specific locations and subtypes of nerves in bone, we are now able to reconcile early studies utilizing denervation models with recent work dissecting the molecular signaling between bone and nerve. In total, sensory innervation functions in bone much as it does elsewhere in the body—to sense and respond to stimuli, including mechanical loading. Similarly, sympathetic nerves regulate autonomic functions related to bone, including homeostatic remodeling and vascular tone. However, more study is required to translate our current knowledge of bone-nerve crosstalk to novel therapeutic strategies that can be effectively utilized to combat skeletal diseases, disorders of low bone mass, and age-related decreases in bone quality.

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Section: Skeletal Innervationmentioning

confidence: 99%

The Role of Nerves in Skeletal Development, Adaptation, and Aging

et al. 2020

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“…Regrowth of sensory nerve fibers is stimulated by NGF, creating pain sensation. NGF also stimulates VEGFA-mediated revascularization and promotes ossification via TrkA-mediated communication between sensory nerves and osteoblasts (Tomlinson et al, 2017;Li et al, 2019; Table 1). Inhibition of TrkA signaling reduces nerve regrowth and revascularization, delaying ossification of fracture calluses (Li et al, 2019).…”

Section: Dynamics Of Bone Vasculature During Fracture Repairmentioning

confidence: 99%

Bone Angiogenesis and Vascular Niche Remodeling in Stress, Aging, and Diseases

Stucker

Chen

Watt

et al. 2020

Front. Cell Dev. Biol.

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The bone marrow (BM) vascular niche microenvironments harbor stem and progenitor cells of various lineages. Bone angiogenesis is distinct and involves tissue-specific signals. The nurturing vascular niches in the BM are complex and heterogenous consisting of distinct vascular and perivascular cell types that provide crucial signals for the maintenance of stem and progenitor cells. Growing evidence suggests that the BM niche is highly sensitive to stress. Aging, inflammation and other stress factors induce changes in BM niche cells and their crosstalk with tissue cells leading to perturbed hematopoiesis, bone angiogenesis and bone formation. Defining vascular niche remodeling under stress conditions will improve our understanding of the BM vascular niche and its role in homeostasis and disease. Therefore, this review provides an overview of the current understanding of the BM vascular niches for hematopoietic stem cells and their malfunction during aging, bone loss diseases, arthritis and metastasis.

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“…Studies have shown the interaction between craniofacial and nervous system, [202][203][204] with recent studies suggesting the importance of sensory nerves to fracture repair and marrow ablation-induced intramembranous bone regeneration, where its impairment leads to delayed bone regeneration. [205][206][207] In addition to these questions, we recognize that the comparisons between embryonic development of membranous bones and postnatal intramembranous bone regeneration will likely require an examination of networks of genes, rather than a select few candidates discussed in this review. Developing the complex network of genes and the cis-regulatory elements that control those genes during embryonic development is being explored via experimental and computational approaches.…”

Section: Discussionmentioning

confidence: 99%

How faithfully does intramembranous bone regeneration recapitulate embryonic skeletal development?

Sumner

2020

Developmental Dynamics

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Postnatal intramembranous bone regeneration plays an important role during a wide variety of musculoskeletal regeneration processes such as fracture healing, joint replacement and dental implant surgery, distraction osteogenesis, stress fracture healing, and repair of skeletal defects caused by trauma or resection of tumors. The molecular basis of intramembranous bone regeneration has been interrogated using rodent models of most of these conditions. These studies reveal that signaling pathways such as Wnt, TGFβ/BMP, FGF, VEGF, and Notch are invoked, reminiscent of embryonic development of membranous bone. Discoveries of several skeletal stem cell/progenitor populations using mouse genetic models also reveal the potential sources of postnatal intramembranous bone regeneration. The purpose of this review is to compare the underlying molecular signals and progenitor cells that characterize embryonic development of membranous bone and postnatal intramembranous bone regeneration.

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Fracture repair requires TrkA signaling by skeletal sensory nerves

Cited by 147 publications

References 61 publications

The Role of Nerves in Skeletal Development, Adaptation, and Aging

The Role of Nerves in Skeletal Development, Adaptation, and Aging

Bone Angiogenesis and Vascular Niche Remodeling in Stress, Aging, and Diseases

How faithfully does intramembranous bone regeneration recapitulate embryonic skeletal development?

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