mechanical signaling via ion channels and neuronal transmitter-receptors

2010 Fiscal Year Final Research Report

• Project/Area Number: 21890071
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Orthopaedic surgery
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: NOUTOMI Takuya Tokyo Medical and Dental University, 歯と骨のGCOE拠点, GCOE拠点形成特任教員 (70542249)
• Project Period (FY): 2009 – 2010
• Keywords: 骨 / 破骨細胞 / イオンチャネル

Research Abstract

Our study focused on one of ion channels, pacemaker channel (HCN) in bone. HCN1 is localized around ruffled border area where osteoclast secretes acid. To elucidate the role of HCNs, HCN1 deficient mice were hired. The role of HCN3 in osteoblasts was investigated.
1 : In HCN1-deficient mice, trabecular bone mass and the structural parameter of Trabecular Number were significantly lower, whereas Trabecular Separation was significantly higher, in HCN1-KO than in wild type (WT). Histomorphometiric indices of bone formation (MAR and BFR/BS) and resorption (Oc.S/BS and Oc.N/BS) were increased.
2 : Patch clamp recordings showed that HCN1-deficiency decreased the activation rate of the hyperpolarization-activated current although the amplitude was same as WT, probably because other HCN subtypes remained intact.
3 : Overexpression of HCN3 by transfecting the gene enhanced proliferation of WT-osteoblasts as measured by total cell number.
4 : Osteoclastic Ih was significantly reduced by knockdown of HCN4, suggesteing that osteoclastic Ih could be generated from HCN1 and HCN4.
The high bone turnover in HCN1-KO was likely to be based on cellular dysfunctions. HCN1 could modulate acid secretion and differentiation in osteoclasts. In addition, lack of HCN1 upregulated expression of HCN3 in osteoblasts. HCN3 may contribute to osteoblastic bone formation.

Research Products

• [Journal Article] Per-1 is a specific clock gene regulated by parathyroid hormone (PTH) signaling in osteoblasts and is functional for the transcriptional events induced by PTH (2011)
  • Author(s): Hanyu R, Hayata T, Nagao M, Saita Y, Hemmi H, Notomi T, Nakamoto T, Schipani E, Knonenbery H, Kaneko K, Kurosawa H, Ezura Y, Noda M
  • Journal Title: Journal of Cellular Biochemistry 112 Pages: 433-438
  • Peer Reviewed
• [Journal Article] Nanogel-based scaffold delivery of prostaglandin E(2) receptor-specific agonist in combination with a low dose of growth factor heals critical-size bone defects in mice (2011)
  • Author(s): Kamolratanakul P, Hayata T, Ezura Y, Kawamata A, Hayashi C, Yamamoto Y, Hemmi H, Nagao M, Hanyu R, Notomi T, Nakamoto T, Amagasa T, Akiyoshi K, Noda M
  • Journal Title: Arthritis and Rheumatism 63 Pages: 1021-1033
  • Peer Reviewed
• [Journal Article] Schnurri-2 deficiency counteracts against bone loss induced by ovariectomy (2011)
  • Author(s): Nagao M, Saita Y, Hanyu R, Hemmi H, Notomi T, Hayata T, Nakamoto T, Nakashima K, Kaneko K, Kurosawa H, Ishii S, Ezura Y, Noda M.
  • Journal Title: Journal of Cellular Physiology 226 Pages: 573-578
  • Peer Reviewed
• [Journal Article] Control of bone remodeling by nervous system. (2010)
  • Author(s): Noda M, Nagao M, Hanyu R, Mizoguchi F, Notomi T, Hayata T, Nakamoto T, Ezura Y.
  • Journal Title: Nervous system and bone 20 Pages: 1801-1805
  • Peer Reviewed
• [Journal Article] Phospholipase C-dependent Ca2+-sensing pathways leading to endocytosis and inhibition of the plasma membrane vacuolar H+-ATPase in osteoclasts (2010)
  • Author(s): Sakai H, Moriura Y, Notomi T, Kawawaki J, Ohnishi K, Kuno M
  • Journal Title: American Journal of Physiology 299 Pages: C570-C578
  • Peer Reviewed
• [Presentation] 遺伝子導入に基づく破骨細胞機能の光学的新規制御システムは陽イオンチャネル依存性膜電位変動により破骨細胞分化を促進する (2010)
  • Author(s): 納富拓也
  • Organizer: 日本骨代謝学会
  • Year and Date: 20100000
• [Presentation] Genetic conversion of osteoclast precursor to be responsive to light-controlled cation channel activation enhances differentiation upon modulation of their membrane potential (2010)
  • Author(s): 納富拓也
  • Organizer: ASBMR 2010 Annual Meeting
  • Year and Date: 20100000
• [Presentation] Pacemaker channel HCN1 affects osteoclast function in vitro and bone remodeling in vivo (2009)
  • Author(s): 納富拓也
  • Organizer: 31^<st> ASBMR Annual Meeting
  • Year and Date: 20090000
• [Presentation] Hyperpolarization-activated cyclic nucleotide modulated channels (HCN) in bone cells : Roles of HCN1 and HCN3 in bone remodeling (2009)
  • Author(s): 納富拓也
  • Organizer: 36^<th> International Congress of Physiological Sciences
  • Year and Date: 20090000
• [Presentation] Pacemaker channel HCN1 affects bone remodeling (2009)
  • Author(s): 納富拓也
  • Organizer: Sokendai International Symposium 2009
  • Place of Presentation: 招待講演
  • Year and Date: 20090000
• [Presentation] ペースメーカーチャネル(HCN1)の破骨細胞機能と骨代謝機構への関与 (2009)
  • Author(s): 納富拓也
  • Organizer: 日本骨代謝学会
  • Year and Date: 20090000
• [Presentation] ペースメーカーチャネル(HCN1)の欠損は高代謝回転による骨量減少を引き起こす (2009)
  • Author(s): 納富拓也
  • Organizer: 骨形態計測学会
  • Year and Date: 20090000
• [Book] 身体トレーニング(宮村実晴編)(運動による骨形態・骨代謝の変化) (2009)
  • Author(s): 納富拓也
  • Total Pages: 430
  • Publisher: 真興交易(株)医書出版部
• [Remarks] ホームページ等