Cell Metab Review—Cao Xu's team reviews the regulation of osteohomeostasis and bone pain by the intraosseous sensory system

The body transmits signals to the brain through sight, hearing, taste, smell and touch, perceives external stimuli such as light, sound, temperature, chemicals and force, makes us recognize the external world, and helps the body make adaptive responses
to seek advantages and avoid harm.
This is called the Exteroception System.
[1]
We have a full understanding
of the external perception system at the molecular receptor and neural circuit levels.
However, the understanding of the body's own internal perception system (Interoceptive System) is just beginning [2].

The endosensory system mainly transmits and regulates the physiological state and energy metabolism signals of various tissues and organs inside the body, such as accelerated heartbeat and increased blood pressure during heartbeat; After a big meal, the gastrointestinal tract expands, peristalsis, and even more difficult to subjectively perceive changes
such as bone mass, energy metabolism, and immune response.
After the vagus visceral sensory nerve transmits these signals to the brain, it is precisely and efficiently integrated and processed by the brain to regulate the autonomic nervous system to make specific responses to maintain the body's internal environmental homeostasis
.

The skeletal system accounts for about 70% of the total volume of the human body, as one of the largest organs in the body, continuous bone remodeling consumes a lot of energy, and plays a non-negligible role in maintaining muscle movement, storing minerals, providing a stable hematopoietic environment and maintaining the balance of energy metabolism in the body Bone also acts as an endocrine organ to regulate the metabolic balance of the whole body [3-5].

Bone is rich in innervation, and the central nervous system regulates bone remodeling and bone marrow stem cell function through sympathetic nerves to maintain bone homeostasis
.
When the disease occurs, the boskeletal sensory nerves transmit pain signals from excessive injury
.
The nutritional support role of sensory nerves on bone has been observed for a long time, but its essential functions - sensing and transmitting changes in bone mass, energy metabolism state, mechanical stimulation and pain stimulation, and the role of the skeletal sensory system in maintaining bone metabolic homeostasis have just been recognized
.

On October 17, 2022, the team of Professor Cao Xu, a lifetime member of the International Chinese Orthopedic Research Society and an orthopedic professor at Johns Hopkins University in the United States, delivered a speech in Cell Metabolism The review of "Skeletal interoception in bone homeostasis and pain", on the basis of introducing the concept of interoception and the latest research progress, systematically summarizes the recent years of intraosseous perception ( Skeletal Interoception) system to maintain bone homeostasis, bone marrow mesenchymal stem cell differentiation and bone and adipose tissue energy conversion; The role of mechanical stimulation and biomaterials in mediating bone regeneration and repair through the intraosseous sensory system was discussed.
The regulatory role of intraosseous sensory system in pathological conditions and the occurrence of bone pain was described.
Finally, the future research direction of intraosseous perception system and its potential translational value for the treatment of orthopedic pain are prospected [6].

The internal perception system was first defined as representing and monitoring the internal organ state of the body, regulating the homeostasis of internal organs, and is the neuroanatomical basis for the central nervous system to participate in maintaining homeostasis, including endosensory signals from various organs, endoreceptors, afferent nerve pathways, central nervous system, and efferent nerve pathways
.
Interoceptive signals include biochemical, mechanical, and electrical signals, and endoceptive signals are distributed through the corresponding endoreceptors (Interoceptor) distributed on the sensory nerves [7].
], through the dorsal root ganglia (DRG) posterior horn of the spinal cord and the nodose ganglia (NG).
Vagus nerve pathways afferent pathways transmit signals to the brain (Figure 1).

Many brain regions in the brain are involved in translating peripheral sensory nerve signals, including the solitary tract nucleus (NTS), thalamus, hypothalamus, and hippocampus hippocampus), etc
.
After being processed by the center, the regulatory signals are transmitted to the corresponding target organs through the autonomic nervous system, that is, sympathetic and parasympathetic nerves, and the functional homeostasis of each organ of the body is maintained through the regulation of autonomic tension [8] (Figure 1).

。

Figure 1 Currently known internal perception system (loop).

(Source: Lv X, et al.
, Cell Metab, 2022).

Continuous bone metabolism maintains the body's normal scaffold structure while providing minerals to the body, a process that is precisely regulated
by the nervous system, just like blood pressure, gastrointestinal motility and blood sugar fluctuations.
The regulation of bone mass, such as blood pressure, gastrointestinal peristalsis, etc.
, are not subjectively perceived
.
When excessive pressure is applied to the bone, bone-related diseases such as osteoarthritis and spinal degeneration can lead to pain, which is the most common symptom of bone disease [9].

Prostaglandin E2 (PGE2) is a classic bone-contributing substance, and gene mutations that edit its transporter and degrading enzymes can lead to inhibition of PGE2 degradation, leading to the development of primary hypertrophic osteoarticular disease (PHA).
[10]
。 In addition, mechanical stimulation can lead to an increase in the concentration of PGE2 in the bone, which means that PGE2 changes with bone mass, but EP4 that knocks out bone cells cannot change bone mass, suggesting that it is suggestive PGE2 may regulate bone through other pathways (Figure 2).

Fig.
2 The intraosseous sensory system maintains intraoskeletal homeostasis

(Source: Lv X, et al.
, Cell Metab, 2022).

Sensory nerves are abundantly innervated to bone, and patients with congenital sensory nerve dysfunction often show bone mass loss and increased fracture incidence (Figure 2).

Studies have found that sensory nerves play a nutritional role in bone by secreting neuropeptides such as SEMA3A and CGRP [11].

Through retrograde tracing and research, it has been proved that the sensory nerve fibers of the bone are transmitted to the nuclei of the brain such as NTS and hypothalamus through the dorsal root ganglia L1-L6 and the dorsal angle of the spinal cord
.
It has also been shown that the bose-sensory nerves can be transmitted to the brain through the DRG dorsal root ganglion spinal cord, and related signals are detected in the hypothalamus [12].

On the other hand, the theory of sympathetic regulatory bone is relatively mature [13].

The authors previously discovered the passage of bone-derived prostaglandin E2 (PGE2) in the Skeletal Interoception -The EP4 axis of the sensory nerve senses changes in bone mass, and signals are transmitted to the VMH nucleus of the hypothalamus through afferent nerve pathways to regulate VMH neuronal CREB Signaling pathways that affect sympathetic nerve activity and thus regulate bone remodeling (Figure 2).

Bone marrow mesenchymal stem cells osteogenic into adipose differentiation function balance and bone and adipose tissue energy metabolism balance
.
The process of bone aging significantly reduces the expression of sensory nerve EP4 receptors, and cannot effectively perceive bone metabolism changes, which is one of the important mechanisms of
bone loss caused by aging.
Related studies were published in Nature Communications [14], JCI [15], and eLife [12]
。

The bone remodeling process is done
by a combination of mesenchymal stem cell-derived osteoblasts and hematopoietic macrophage-derived osteoclasts.
Osteoclast-derived TGFB1 and IGF1 promote bone formation
by recruiting mesenchymal stem cells for osteogenic differentiation.
The process of bone formation is also accompanied by the pdgfbb secreted by osteoclast precursor cells to attract H-type blood vessels to grow and promote osteogenesis
.
Processes such as bone metabolism processes, stem cell proliferation and differentiation, and matrix synthesis that last throughout life consume a lot of energy
.
Bone tissue mainly consumes glucose, and patients with anorexia or metabolic abnormalities may present with bone growth arrest or loss, and abnormal bone energy metabolism can also lead to systemic energy metabolism homeostasis
.

The hypothalamus plays an important role in regulating energy metabolism throughout the body (Figure 3).

Traditionally, the hypothalamic-pituitary-target organ axis, as an important component of neuroendocrine regulation, precisely regulates the energy metabolism homeostasis of bones and other organs [16].

ARC nucleus is the lowest nucleus of the hypothalamus located in the blood-brain barrier junction area, ARC nucleus mainly collects afferent signals, secretes various neuropeptides, and transmits signals to other nuclei for systemic energy metabolism regulation
.
The ARC nucleus is mainly composed of anabolic AgRP/NPY neurons and pro-catabolic POMC/CART neurons, which play very different roles in bone metabolism (Fig 3）
。 NPY is expressed in AgRP/NPY neurons, and studies have proved that NPY systemic knockout mice show high bone mass
.
NPY has 6 corresponding receptors distributed throughout the body, systemic or conditioned knockout Y2R also shows high bone mass, but central knockout Y1R has no obvious change in bone mass, and in bone knockout Y1R increases bone mass, suggesting that NPY may function
through bone Y1R.
It was found that sensory nerve knockout of EP4 receptors can significantly increase the expression of NPY in the hypothalamic ARC nucleus, resulting in increased accumulation of medullary cavity and peripheral adipose tissue and decreased bone mass.
Peripheral injection of SW033291 can inhibit the NPY expression of ARC, promote the decomposition of adipose tissue, and increase bone mass [12] (Fig.
3).
）
。 It is suggested that the PGE2-EP4 intraosseous sensory system can regulate bone and fat metabolism homeostasis by regulating the hypothalamic neuroendocrine system (Fig.
3).

Figure 3 The intraosseous sensory system regulates the neuroendocrine factor NPY to balance metabolism between bone and fat

(Source: Lv X, et al.
, Cell Metab, 2022).

The energy requirements of mammals and the energy metabolism processes of glycolipid proteins are regulated
by the sensing system.
The body's major energy organs transmit energy metabolism to the center by transmitting vagus and spinal cord afferent neural pathways, which in turn maintain energy homeostasis
by regulating the activity of the autonomic nervous system.
Adipose tissue gastrointestinal tract and pancreas have rich innervation, through their respective endosensory systems to regulate feeding behavior and glycolipid metabolism homeostasis
.
The intraosseous sensory system helps maintain the energy requirements
of bone metabolic activity by coordinating energy metabolism throughout the body.

Under pathological conditions, bone homeostasis is out of balance, inflammatory cells invade bone and osteochondral tissue, secrete a large number of inflammatory factors leading to pain-related phenotypes, abnormal activation of osteoclasts, and a large number of osteoclast precursor cells secrete Netrin1 to induce nociceptive sensory nerves to grow into the cavitary endplate and subchondral bone, causing lower back pain and joint pain
.
Related studies were published in Nature Communications [17], JCI [18] (Figure 4).

。 At the same time, sensory nerves grow in the endplate and subchondral bone and activate Nav1.
8-positive nociceptive sensory neuronal activation by locally sensing inflammatory factors including PGE2, resulting in pain [19] (Figure 4).
）
。 Studies have also found that low doses of celecoxib and biomaterials with divalent metal ions implanted in bone defects can effectively maintain the concentration of PGE2 in bone and degenerative cavitated bony endplates, activate the intraosseous perception system, maintain bone homeostasis, and promote bone repair [20, 21].

Therefore, in-depth research on the mechanisms of the intraosseous sensory system can help provide a new perspective on the treatment of bone-related diseases (Figure 4).

Figure 4 Intraosseous perception system of skeletal homeostasis and imbalance (under pathological conditions).

(Source: Lv X, et al.
, Cell Metab, 2022).

In addition to bones and joints, other tissues of the motor system including muscles, tendons, ligaments, etc.
are also related to the central nervous system, so it is reasonable to look forward to further understanding
of the perceptual system within the motor system.
Given the complex and intimate connection between bone and nervous system, in addition to the prostaglandin E2 (PGE2) secreted by osteoblasts through the sensory nerve EP4 The mediators through which cells other than the receptor are linked to the intraosseous sensory system deserve further exploration
.
Whether other brain regions of the central nervous system besides the hypothalamus including the hippocampus, thalamus, and amygdala are involved in receiving and processing perceptual signals within the motor system still need to be further studied
.
More translational research lies in how the intraosseous sensory system works under various pathological conditions, produces pain, regulates and maintains local homeostasis, and even affects mood, which are worth looking forward to
in the future.

The proposal and confirmation of the concept of intraosseous sensory system breaks the traditional thinking framework that bone aging is mainly caused by local osteogenesis and osteoclastic system disorders of bone metabolism, which further recognizes the function of the endosperous system, and also significantly promotes the research level
in the field of nervous system regulation of bone.
The intraosseous sensory system strengthens the connection between bone and other organs, provides sufficient theoretical basis for regulating the homeostasis and energy metabolism balance of the whole body, and points out the future research and development direction
of bone research.

Original link: https://doi.
org/10.
1016/j.
cmet.
2022.
09.
025

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