TRPM8 channel inhibitor-encapsulated hydrogel as a tunable surface for bone tissue engineering

Acharya, Tusar Kanta; Kumar, Satish; Tiwari, Nikhil; Ghosh, Arijit; Tiwari, Ajay; Pal, Subhashis; Majhi, Rakesh Kumar; Kumar, Ashutosh; Das, Rashmita; Singh, Asmita; Maji, Pradip K.; Chattopadhyay, Naibedya; Goswami, Luna; Goswami, Chandan

doi:10.1038/s41598-021-81041-w

Cited by 13 publications

(21 citation statements)

References 37 publications

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“…However, the way temperature regulation is related to bone in this context is unclear, and the mechanism of low bone mass in Trpm8-KO mice will need to be determined in future work. Some in vitro evidence suggests human osteoblast-like cells and murine osteoblast cells express Trpm8 , but the functional role in bone in vivo is unclear [ 29 , 30 ]. Although the deletion of other Trp channels, such as Trpv1 [ 31 ] and Trpv5 [ 32 ], has been reported to induce bone loss in animal models, there is a lack of data exploring the physiological role of TRPM8 in skeletal homeostasis.…”

Section: Discussionmentioning

confidence: 99%

TRPM8 modulates temperature regulation in a sex-dependent manner without affecting cold-induced bone loss

et al. 2021

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Trpm8 (transient receptor potential cation channel, subfamily M, member 8) is expressed by sensory neurons and is involved in the detection of environmental cold temperatures. TRPM8 activity triggers an increase in uncoupling protein 1 (Ucp1)-dependent brown adipose tissue (BAT) thermogenesis. Bone density and marrow adipose tissue are both influenced by rodent housing temperature and brown adipose tissue, but it is unknown if TRPM8 is involved in the co-regulation of thermogenesis and bone homeostasis. To address this, we examined the bone phenotypes of one-year-old Trpm8 knockout mice (Trpm8-KO) after a 4-week cold temperature challenge. Male Trpm8-KO mice had lower bone mineral density than WT, with smaller bone size (femur length and cross-sectional area) being the most striking finding, and exhibited a delayed cold acclimation with increased BAT expression of Dio2 and Cidea compared to WT. In contrast to males, female Trpm8-KO mice had low vertebral bone microarchitectural parameters, but no genotype-specific alterations in body temperature. Interestingly, Trpm8 was not required for cold-induced trabecular bone loss in either sex, but bone marrow adipose tissue in females was significantly suppressed by Trpm8 deletion. In summary, we identified sex differences in the role of TRPM8 in maintaining body temperature, bone microarchitecture and marrow adipose tissue. Identifying mechanisms through which cold temperature and BAT influence bone could help to ameliorate potential bone side effects of obesity treatments designed to stimulate thermogenesis.

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Section: Discussionmentioning

confidence: 99%

TRPM8 modulates temperature regulation in a sex-dependent manner without affecting cold-induced bone loss

et al. 2021

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“…With advancements in biomaterials, recapitulating such a phenomenon in vitro has garnered significant interest in current times. We have previously introduced a novel polysaccharide-based hydrogel CMT:HEMA 13 as an effective matrix for skin 14 and bone 15 tissue engineering. In order to deliver TRPV1 modulators in a controlled manner, we chose to encapsulate TRPV1 modulators in CMT:HEMA, which can get degraded over time and ensure slow release of drugs encapsulated within it.…”

Section: Resultsmentioning

confidence: 99%

“…The surface microstructure of the hydrogel revealed a highly interconnected, porous matrix that allows for cells to efficiently attach and proliferate. 15 …”

Section: Resultsmentioning

confidence: 99%

“…The surface microstructure of the hydrogel revealed a highly interconnected, porous matrix that allows for cells to efficiently attach and proliferate. 15 In Vitro Sustained Release of Capsaicin from the CMT:HEMA Hydrogel. A major route of pharmaceutical drug administration (oral) is limited by nonspecific targeting, short half-lives, and reduced circulation time.…”

Section: ■ Resultsmentioning

confidence: 99%

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Hydrogel-Mediated Release of TRPV1 Modulators to Fine Tune Osteoclastogenesis

et al. 2022

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Bone defects, including bone loss due to increased osteoclast activity, have become a global health-related issue. Osteoclasts attach to the bone matrix and resorb the same, playing a vital role in bone remodeling. Ca 2+ homeostasis plays a pivotal role in the differentiation and maturation of osteoclasts. In this work, we examined the role of TRPV1, a nonselective cation channel, in osteoclast function and differentiation. We demonstrate that endogenous TRPV1 is functional and causes Ca 2+ influx upon activation with pharmacological activators [resiniferatoxin (RTX) and capsaicin] at nanomolar concentration, which enhances the generation of osteoclasts, whereas the TRPV1 inhibitor (5′-IRTX) reduces osteoclast differentiation. Activation of TRPV1 upregulates tartrate-resistant acid phosphatase activity and the expression of cathepsin K and calcitonin receptor genes, whereas TRPV1 inhibition reverses this effect. The slow release of capsaicin or RTX at a nanomolar concentration from a polysaccharide-based hydrogel enhances bone marrow macrophage (BMM) differentiation into osteoclasts whereas release of 5′-IRTX, an inhibitor of TRPV1, prevents macrophage fusion and osteoclast formation. We also characterize several subcellular parameters, including reactive oxygen (ROS) and nitrogen (RNS) species in the cytosol, mitochondrial, and lysosomal profiles in BMMs. ROS were found to be unaltered upon TRPV1 modulation. NO, however, had elevated levels upon RTX-mediated TRPV1 activation. Capsaicin altered mitochondrial membrane potential (ΔΨm) of BMMs but not 5′-IRTX. Channel modulation had no significant impact on cytosolic pH but significantly altered the pH of lysosomes, making these organelles less acidic. Since BMMs are precursors for osteoclasts, our findings of the cellular physiology of these cells may have broad implications in understanding the role of thermosensitive ion channels in bone formation and functions, and the TRPV1 modulator-releasing hydrogel may have application in bone tissue engineering and other biomedical sectors.

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“…Nanotechnologies could also be of help in the way of diagnosis probes and for tissue specific drug delivery. In fact, a carbohydrate polymer-based hydrogel, with a nanofiber-like structure, has already been described for a long-lasting and optimal delivery of the TRPM8 antagonist AMTB [193].…”

Section: Perspectivesmentioning

confidence: 99%

TRPM8 Channels: Advances in Structural Studies and Pharmacological Modulation

Izquierdo

Martı́n-Martı́nez

Gómez-Monterrey

et al. 2021

IJMS

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The transient receptor potential melastatin subtype 8 (TRPM8) is a cold sensor in humans, activated by low temperatures (>10, <28 °C), but also a polymodal ion channel, stimulated by voltage, pressure, cooling compounds (menthol, icilin), and hyperosmolarity. An increased number of experimental results indicate the implication of TRPM8 channels in cold thermal transduction and pain detection, transmission, and maintenance in different tissues and organs. These channels also have a repercussion on different kinds of life-threatening tumors and other pathologies, which include urinary and respiratory tract dysfunctions, dry eye disease, and obesity. This compendium firstly covers newly described papers on the expression of TRPM8 channels and their correlation with pathological states. An overview on the structural knowledge, after cryo-electron microscopy success in solving different TRPM8 structures, as well as some insights obtained from mutagenesis studies, will follow. Most recently described families of TRPM8 modulators are also covered, along with a section of molecules that have reached clinical trials. To finalize, authors provide an outline of the potential prospects in the TRPM8 field.

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TRPM8 channel inhibitor-encapsulated hydrogel as a tunable surface for bone tissue engineering

Cited by 13 publications

References 37 publications

TRPM8 modulates temperature regulation in a sex-dependent manner without affecting cold-induced bone loss

TRPM8 modulates temperature regulation in a sex-dependent manner without affecting cold-induced bone loss

Hydrogel-Mediated Release of TRPV1 Modulators to Fine Tune Osteoclastogenesis

TRPM8 Channels: Advances in Structural Studies and Pharmacological Modulation

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