Transient receptor potential vanilloid 1 and 4 double knockout leads to increased bone mass in mice

Nishimura, Haruki; Kawasaki, Makoto; Tsukamoto, Manabu; Menuki, Kunitaka; Suzuki, Hitoshi; Matsuura, Takanori; Baba, Kazuhiko; Motojima, Yasuhito; Fujitani, Teruaki; Ohnishi, Hideo; Yamanaka, Yoshiaki; Kosugi, Kenji; Okada, Yasuaki; Tokuda, Kotaro; Tajima, Takafumi; Yoshioka, Toru; Okimoto, Nobukazu; Ueta, Yoichi

doi:10.1016/j.bonr.2020.100268

Cited by 13 publications

(12 citation statements)

References 48 publications

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“…8 Reduced osteoclastogenesis due to TRPV1 KO consequently results in increased bone mass. 27 In conditions involving low bone density, increased osteoclast activities have been shown to be a driving force, which can be rescued upon inhibition of TRPV1, thereby suggesting a pharmacologically active premise of bone remodeling via TRPV1 regulation. 28 In this study, we found that endogenous TRPV1 expression in BMM increases upon stimulation with RANKL for 3 days, indicating that TRPV1 is upregulated during differentiation of BMMs.…”

Section: ■ Discussionmentioning

confidence: 99%

“…Deletion of TRPV1 in mice leads to impairments in osteoclastogenesis and fracture healing . Reduced osteoclastogenesis due to TRPV1 KO consequently results in increased bone mass . In conditions involving low bone density, increased osteoclast activities have been shown to be a driving force, which can be rescued upon inhibition of TRPV1, thereby suggesting a pharmacologically active premise of bone remodeling via TRPV1 regulation …”

Section: Discussionmentioning

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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Section: ■ Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Hydrogel-Mediated Release of TRPV1 Modulators to Fine Tune Osteoclastogenesis

et al. 2022

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“…In addition to the synovial invasion, TRPV4 has also been shown to mediate Ca 2+ influx and chondrocyte apoptosis in osteoarthritis models [ 114 ]. In addition to TRPV5, TRPV4 has also been shown to impact the differentiation and activity of osteoclasts [ 115 , 116 ]. It was shown that TRPV4 mediates Ca 2+ influx into rat osteoclasts and provides sufficient [Ca 2+ ] i to maintain RANKL-induced osteoclast differentiation [ 117 ].…”

Section: Transient Receptor Potential (Trp) Channelsmentioning

confidence: 99%

Calcium-Permeable Channels Cooperation for Rheumatoid Arthritis: Therapeutic Opportunities

Liang

Yin

et al. 2022

Biomolecules

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Rheumatoid arthritis is a common autoimmune disease that results from the deposition of antibodies–autoantigens in the joints, leading to long-lasting inflammation. The main features of RA include cartilage damage, synovial invasion and flare-ups of intra-articular inflammation, and these pathological processes significantly reduce patients’ quality of life. To date, there is still no drug target that can act in rheumatoid arthritis. Therefore, the search for novel drug targets has become urgent. Due to their unique physicochemical properties, calcium ions play an important role in all cellular activities and the body has evolved a rigorous calcium signaling system. Calcium-permeable channels, as the main operators of calcium signaling, are widely distributed in cell membranes, endoplasmic reticulum membranes and mitochondrial membranes, and mediate the efflux and entry of Ca2+. Over the last century, more and more calcium-permeable channels have been identified in human cells, and the role of this large family of calcium-permeable channels in rheumatoid arthritis has gradually become clear. In this review, we briefly introduce the major calcium-permeable channels involved in the pathogenesis of RA (e.g., acid-sensitive ion channel (ASIC), transient receptor potential (TRP) channel and P2X receptor) and explain the specific roles and mechanisms of these calcium-permeable channels in the pathogenesis of RA, providing more comprehensive ideas and targets for the treatment of RA.

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“…For example, TRPV4-mediated Ca 2+ influx is required for osteoclast differentiation by triggering nuclear factor of activated T-cells cytoplasmic 1 (NFATC1)-dependent gene expression (46). Moreover, knockout of TRPV4 or TRPV1 increased bone mass in a mouse model (47). Therefore, antagonizing TRPV4 may become a novel strategy to prevent or treat MM-associated bone destruction.…”

Section: Trp Channels In the Bone Destruction Of MMmentioning

confidence: 99%

Transient receptor potential channels in multiple myeloma (Review)

Meng

2022

Oncol Lett

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Multiple myeloma is the second most commonly diagnosed hematologic malignancy. As an incurable disease, the molecular mechanisms underlying its many aspects remain unclear. Intracellular calcium ion is an essential signaling molecule that modulates malignant cell behavior, and abnormal regulation of cellular calcium homeostasis may promote cancer cell survival and induce drug resistance. Transient receptor potential (TRP) cation channels are a superfamily of non-selective Ca 2+ -permeable channels that regulate intracellular calcium signaling and are involved in the regulation of various characteristics of cancer cells. Emerging evidence shows a close connection between TRP channels and multiple myeloma. This review summarizes the roles of TRP channels in multiple myeloma progression, metastasis, bone destruction, and drug resistance. TRPV1 and TRPV2 orchestrate the progression of multiple myeloma, while TRPM7 promotes myeloma cell dissemination and spreading. TRPV2 and TRPV4, that activate osteoclasts, contribute to the development of osteolytic bone disease caused by multiple myeloma. Both TRPV1 inhibition and TRPV2 activation synergize with bortezomib in the chemotherapy of multiple myeloma, and TRPC1 can determine the responsiveness of multiple myeloma to MTI-101, a cyclic beta-hairpin peptide.Antagonizing TRPA1 can alleviate bortezomib-induced painful peripheral neuropathy. Future studies in this field may identify certain TRP channels as markers or therapeutic targets for predicting the prognosis, preventing progression, and improving drug responsiveness in patients with multiple myeloma.

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Transient receptor potential vanilloid 1 and 4 double knockout leads to increased bone mass in mice

Cited by 13 publications

References 48 publications

Hydrogel-Mediated Release of TRPV1 Modulators to Fine Tune Osteoclastogenesis

Hydrogel-Mediated Release of TRPV1 Modulators to Fine Tune Osteoclastogenesis

Calcium-Permeable Channels Cooperation for Rheumatoid Arthritis: Therapeutic Opportunities

Transient receptor potential channels in multiple myeloma (Review)

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