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influences the construction of muscle tissue by directing interactions that maintain bone homeostasis by precisely
the orientation of muscle fibers, delineating muscle bundle regulating osteoblast and osteoclast activity.
boundaries, and even shaping the overall morphology of In conclusion, innervation in the MSK system not
the muscle to avoid the formation of disorganized cell only provides electrical stimulation signals but is also
clusters. At the same time, the loss of innervation is the deeply involved in the physiological functions of muscle
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most important cause of muscle atrophy (both wasting and bone. The incorporation of the nervous system can
atrophy and neurogenic atrophy). This highlights the dual further enrich the pathology model of MSK organoids.
critical role of nerves on muscles. On the one hand, nerves However, researchers are currently unable to extract
provide essential trophic factors that maintain muscle mass primary functional neurons from patients, which pose
and metabolic activity. On the other hand, the electrical a significant challenge to the study of NMOs. To address
activity of nerves is a central stimulus that maintains the this issue, researchers have turned to patient-derived iPSCs
balance between protein synthesis and degradation and as an alternative. By inducing iPSCs through different
inhibits apoptotic signaling within the muscle. At the core processes, researchers can differentiate them into muscle
of many diseases of the MSK system lies, a disruption of cells and neurons, successfully forming NMOs. These
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the NMJ or a lesion of the nerves/muscles themselves, for organoids effectively mimic muscle weakness and NMJ
example, ALS, spinal muscular atrophy, and myasthenia defects, serving as models for neuromuscular diseases and
gravis. Simple muscle organoids lacking the nervous system platforms for screening therapeutic drugs. They provide
cannot accurately mimic key pathological processes, such a valuable platform for studying disease mechanisms and
as secondary muscle damage, due to neurogenesis. Martins potential therapeutic interventions.
et al. induced hPSCs to generate spinal cord neurons and
skeletal muscle cells in 3D culture, which were able to self- 5.1.3. Deficiency of the immune system
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organize and form NMOs containing functional NMJ. Whereas traditional anatomy views the MSK system
This organoid model provides a powerful tool for exploring as a mechanical support structure and categorizes the
the developmental process of functional neuromuscular immune system as a defense network, contemporary
networks and the underlying communication mechanisms. research over the past two decades confirms their profound
Notably, in this type of organoid, sustained innervation integration through osteoimmunology. In the muscle
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is equally necessary to maintain the long-term survival microenvironment, the development and repair of muscle
of muscle fibers and prevent their degeneration, further cells are mainly regulated by T cells and macrophages.
confirming the indispensability of nerves in muscle T cells express amphiregulin, epidermal growth factor
homeostasis. receptor, and suppression of tumorigenicity 2, which
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In recent years, it has been reported that the nervous promote myotube maturation and contractile function.
system not only regulates muscle activity but also directly Macrophages, on the other hand, secrete factors such as
affects bone development and metabolism through a IGF-1 and TGF-β through the M2 type to reduce fibrosis
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complex signaling network. Among them, sympathetic and drive functional myofiber formation. In the skeletal
nerves mainly act through the release of norepinephrine microenvironment, the bone marrow serves as the core
and neuropeptide Y. 234-236 These neurotransmitters have hematopoietic site, providing a symbiotic ecological niche
been shown to modulate osteoblast activity and osteoclast- for immune cells (T/B cells, macrophages, and granulocytes)
mediated bone resorption. In contrast, parasympathetic and skeletal cells (osteoblasts, osteoclasts, and osteocytes).
nerves act through ACh and vasoactive intestinal Among them, the RANKL/receptor activator of nuclear
peptide. 237-239 Significant cholinergic innervation is observed factor-κB (RANK)/OPG pathway is a key hub for bone
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during skeletal growth and development and during immunoregulation. RANKL was initially discovered in
fracture healing. These neurotransmitters not only promote activated T cells and regulates T-cell function. Subsequent
the proliferation of osteoblasts but also induce apoptosis studies have shown that osteoblasts also express high levels
of osteoclasts, thus maintaining the dynamic balance of RANKL, and that RANKL-RANK binding directly
between bone formation and bone resorption. The role of drives osteoclast differentiation, activation, and survival,
sensory nerves in bone regulation is also not negligible. leading to bone resorption.
Calcitonin gene-related peptide, as the main transmitter In addition to T cells, cytokines secreted by other
of sensory nerves, can significantly increase the expression immune cells profoundly affect the balance of bone
level of osteogenic differentiation markers in BMSCs, formation and resorption by modulating this pathway.
suggesting that it may be involved in the process of bone Neutrophils infiltrate during the acute inflammatory
repair through the promotion of differentiation of BMSCs phase, releasing reactive oxygen species and proteases
to osteoblasts. 240,241 Together, these neuromodulatory that directly damage bone tissue and indirectly accelerate
mechanisms constitute a complex network of neural-bone bone resorption through pro-inflammatory factors.
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Volume 1 Issue 3 (2025) 18 doi: 10.36922/OR025280024