Sympathetic Innervation Regulates Osteocyte‐Mediated Cortical Bone Resorption during Lactation

Abstract

Bone undergoes constant remodeling by osteoclast bone resorption coupled with osteoblast bone formation at the bone surface. A third major cell type in the bone is osteocytes, which are embedded in the matrix, are well-connected to the lacunar network, and are believed to act as mechanical sensors. Here, it is reported that sympathetic innervation directly regulates lacunar osteocyte-mediated bone resorption inside cortical bone. It is found that sympathetic activity is elevated in different mouse models of bone loss, including lactation, ovariectomy, and glucocorticoid treatment. Further, during lactation elevated sympathetic outflow induces netrin-1 expression by osteocytes to further promote sympathetic nerve sprouting in the cortical bone endosteum in a feed-forward loop. Depletion of tyrosine hydroxylase-positive (TH + ) sympathetic nerves ameliorated osteocyte-mediated perilacunar bone resorption in lactating mice. Moreover, norepinephrine activates 𝜷-adrenergic receptor 2 (Adrb2) signaling to promote secretion of extracellular vesicles (EVs) containing bone-degrading enzymes for perilacunar bone resorption and inhibit osteoblast differentiation. Importantly, osteocyte-specific deletion of Adrb2 or treatment with a 𝜷-blocker results in lower bone resorption in lactating mice. Together, these findings show that the sympathetic nervous system promotes osteocyte-driven bone loss during lactation, likely as an adaptive response to the increased energy and mineral demands of the nursing mother.

Aging decreases osteocyte lacunar-canalicular turnover in female C57BL/6 mice

“…Osteocyte lacunar-canalicular system (LCS) turnover has been of high research interest as a possible contributor to age-related changes in bone fracture resistance 3,4,17,18,34,63,64 . Extensive evidence indicates that age reduces osteocyte viability and mechanosensitivity 7,8,14,25,[65][66][67][68][69] and truncates lacunar and canalicular dimensions and connectivity 20,21,62,[70][71][72][73] . These changes imply that there is a decrease in LCS turnover in aging, which could have impacts to osteocyte mechanosensitivity and bone matrix quality 17,19,20,30,35,42,74 .…”

“…The impacts of osteocyte LCS turnover (alternatively termed perilacunar or lacunar-canalicular remodeling) on the aging skeleton are uncertain, in part because the percentage of osteocytes that engage in bone resorption or mineralization alongside the LCS is unknown 3,4,17,18 . As witnessed in studies of rodent lactation or PTH treatment, osteocytes can expand lacunae and canaliculi through production of acids and proteases 17,18,[23][24][25][26][27][28][29][30][31][32][33] . These pores can then recover to their original size, which implies bone remineralization 24,31 .…”

Skeletal interoception in osteoarthritis

“… 92 Generally, the activation of the SNS leads to bone resorption while suppressing bone formation, whereas the PNS exerts contrasting effects. 93 Mechanistically, the SNS releases NE, which bind to α1, α2, β1, β2, β3-AR to exerts its physiological effects. The binding of NE with β2-AR on OBs inhibits their proliferation and differentiation, while its binding with α2-AR on OBs promotes their RANKL expression, thereby mediating bone resorption.…”

Psychological stress disturbs bone metabolism via miR-335-3p/Fos signaling in osteoclast

“…Former research suggested that psychological stress can stimulate the autonomic nerves or the central nervous system to disrupt the activation of sympathetic nerves(Kondo & Togari, 2003; Ma et al, 2023) and the endocrine homeostasis(Raison & Miller, 2003) respectively. They alters the levels of neurotransmitters(Chen & Wang, 2017; Foertsch et al, 2017; Guo et al, 2023; Khosla et al, 2018; Teong et al, 2017), neuropeptides(Baldock et al, 2014; Ng & Chin, 2021), hormones(Hasan et al, 2012; Henneicke et al, 2017), related biomolecules, and their corresponding receptors in vivo , so as to affect the activations of several signaling pathways. Therefore, it contributes to the increased osteoclast activity, decreased osteoblast activity, and promoted bone matrix degradation, ultimately leading to bone loss.…”