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Osteoblasts are inherently programmed to repel sensory innervation

Luís Leitão^1,2,3, Estrela Neto^1,2, Francisco Conceição^1,2,3

¹1Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, 4200-135 Porto, Portugal.

|May 22, 2020

Abstract:

Tissue innervation is a complex process controlled by the expression profile of signaling molecules secreted by tissue-resident cells that dictate the growth and guidance of axons. Sensory innervation is part of the neuronal network of the bone tissue with a defined spatiotemporal occurrence during bone development. Yet, the current understanding of the mechanisms regulating the map of sensory innervation in the bone tissue is still limited. Here, we demonstrated that differentiation of human mesenchymal stem cells to osteoblasts leads to a marked impairment of their ability to promote axonal growth, evidenced under sensory neurons and osteoblastic-lineage cells crosstalk. The mechanisms by which osteoblast lineage cells provide this nonpermissive environment for axons include paracrine-induced repulsion and loss of neurotrophic factors expression. We identified a drastic reduction of NGF and BDNF production and stimulation of Sema3A, Wnt4, and Shh expression culminating at late stage of OB differentiation. We noted a correlation between Shh expression profile, OB differentiation stages, and OB-mediated axonal repulsion. Blockade of Shh activity and signaling reversed the repulsive action of osteoblasts on sensory axons. Finally, to strengthen our model, we localized the expression of Shh by osteoblasts in bone tissue. Overall, our findings provide evidence that the signaling profile associated with osteoblast phenotype differentiating program can regulate the patterning of sensory innervation, and highlight osteoblast-derived Shh as an essential player in this cue-induced regulation.

Insights

Osteoblasts, developing bone cells, create a signaling environment that repels sensory nerve growth by reducing nerve growth factors and increasing repulsive signals like Shh (Sonic hedgehog). This regulates sensory innervation in bone.

Area of Science:

Bone biology
Neuroscience
Cell signaling

Background:

Bone tissue is innervated by sensory neurons, crucial for skeletal development and function.
The mechanisms regulating sensory nerve mapping in bone remain poorly understood.
Mesenchymal stem cell differentiation into osteoblasts influences the bone microenvironment.

Purpose of the Study:

To investigate how osteoblast differentiation affects sensory innervation in bone.
To identify signaling molecules involved in the crosstalk between osteoblasts and sensory neurons.
To elucidate the role of osteoblast-derived signals in regulating sensory axon guidance.

Main Methods:

Co-culture of human mesenchymal stem cells and sensory neurons.
Analysis of gene and protein expression during osteoblast differentiation (NGF, BDNF, Sema3A, Wnt4, Shh).
Functional assays blocking Shh signaling to assess axonal repulsion.
In situ localization of Shh expression in bone tissue.

Main Results:

Osteoblast differentiation impairs axonal growth promotion and induces repulsion of sensory neurons.
Reduced expression of neurotrophic factors (NGF, BDNF) and increased expression of repulsive cues (Sema3A, Wnt4, Shh) occur during osteoblast differentiation.
Shh expression correlates with osteoblast differentiation stage and mediates axonal repulsion.
Blocking Shh signaling reverses the repulsive effect of osteoblasts on sensory axons.
Shh is expressed by osteoblasts in bone tissue.

Conclusions:

Osteoblast differentiation establishes a signaling milieu that actively shapes sensory innervation patterns in bone.
Osteoblast-derived Shh is a key regulator of sensory axon repulsion and patterning during bone development.
Understanding this crosstalk is vital for comprehending bone innervation and developing therapeutic strategies.

Read full analysis

Keywords:

Bone Homeostasis Neurophysiology

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