Neuromodulation of bone: Role of different peptides and their interactions (Review)

Abstract

Our understanding of the skeletal system has been expanded upon the recognition of several neural pathways that serve important roles in bone metabolism and skeletal homeostasis, as bone tissue is richly innervated. Considerable evidence provided by in vitro, animal and human studies have further elucidated the importance of a host of hormones and local factors, including neurotransmitters, in modulating bone metabolism and osteo-chondrogenic differentiation, both peripherally and centrally. Various cells of the musculoskeletal system not only express receptors for these neurotransmitters, but also influence their endogenous levels in the skeleton. As with a number of physiological systems in nature, a neuronal pathway regulating bone turnover will be neutralized by another pathway exerting an opposite effect. These neuropeptides are also critically involved in articular cartilage homeostasis and pathogenesis of degenerative joint disorders, such as osteoarthritis. In the present Review, data on the role of several neuronal populations in nerve-dependent skeletal metabolism is examined, and the molecular events involved are explored, which may reveal broader relationships between two apparently unrelated organs.

Pre-proenkephalin 1 is Downregulated Under Unloading and is Involved in Osteoblast Biology

“…Neuropeptides are involved in the regulation of bone metabolism, influencing the activity of bone cells, including osteoblasts, osteoclasts, and osteocytes [ 1 , 2 , 34 , 35 ]. Nevertheless, the role in bone of opioids, a specific class of neuropeptides, is still partially unclear and the complexity of their signalling pathway further complicates the scenario.…”

“…Recent research has shown that neuropeptides affect the functions of bone cells playing an essential role in the metabolism of the skeletal tissues [ 1 , 2 ]. Pre-proenkephalin 1 ( Penk1 ) is a gene encoding a pro-neuropeptide that is proteolytically processed to generate the following enkephalins: [Met]-enkephalin, [Met]-enkephalin extended sequence, and [Leu]-enkephalin, all belonging to the family of opioid peptides that are endogenous ligands for opioid receptors having potent analgesic properties [ 3 ].…”

Interoceptive regulation of skeletal tissue homeostasis and repair

“…49 Furthermore, sensory nerve fibers are more densely innervated in the epiphysis compared to the metaphysis, and are mainly restricted to vascularized CD31 + Haversian canals. 1,50 Sensory nerves can be classified by their receptors and channels, such as toll-like receptors, tyrosine kinase receptors, transient receptor potential ion channels, and mechanosensitive Piezo channels. 44,51 These receptors and channels initiate intracellular signaling and the release of neuropeptides.…”

Recent advances in mass spectrometry analysis of neuropeptides

“…Neuropeptides impact a large and diverse array of physiological processes (Insel, 2010; Mills et al, 2020; Neumann & Landgraf, 2012; Steinhoff et al, 2014; Wang et al, 2021; Xu et al, 2020). Functional elucidation is not trivial notably due to neuropeptide co‐transmission capabilities (Nusbaum et al, 2017) and pleiotropic nature (Souza‐Moreira et al, 2011).…”