Abstract:
:Bone morphogenetic proteins (BMPs) were first described over 50 years ago as potent inducers of ectopic bone formation when administrated subcutaneously. Preclinical studies have extensively examined the osteoinductive properties of BMPs in vitro and new bone formation in vivo. BMPs (BMP-2, BMP-7) have been used in orthopedics over 15 years. While osteogenic function of BMPs has been widely accepted, our previous studies demonstrated that loss-of-function of BMP receptor type IA (BMPR1A), a potent receptor for BMP-2, increased net bone mass by significantly inhibiting bone resorption in mice, indicating a positive role of BMP signaling in bone resorption. The physiological role of BMPs (i.e. osteogenic vs. osteoclastogenic) is still largely unknown. The purpose of this study was to investigate the physiological role of BMP signaling in endogenous long bones during adult stages. For this purpose, we conditionally and constitutively activated the Smad-dependent canonical BMP signaling thorough BMPR1A in osteoblast lineage cells using the mutant mice (Col1CreER™:caBmpr1a). Because trabecular bones were largely increased in the loss-of-function mouse study for BMPR1A, we hypothesized that the augmented BMP signaling would affect endogenous trabecular bones. In the mutant bones, the Smad phosphorylation was enhanced within physiological level three-fold while the resulting gross morphology, bodyweights, bone mass/shape/length, serum calcium/phosphorus levels, collagen cross-link patterns, and healing capability were all unchanged. Interestingly, we found; 1) increased expressions of both bone formation and resorption markers in femoral bones, 2) increased osteoblast and osteoclast numbers together with dynamic bone formation parameters by trabecular bone histomorphometry, 3) modest bone architectural phenotype with reduced bone quality (i.e. reduced trabecular bone connectivity, larger diametric size but reduced cortical bone thickness, and reduced bone mechanical strength), and 4) increased expression of SOST, a downstream target of the Smad-dependent BMPR1A signaling, in the mutant bones. This study is clinically insightful because gain-of-function of BMP signaling within a physiological window does not increase bone mass while it alters molecular and cellular aspects of osteoblast and osteoclast functions as predicted. These findings help explain the high-doses of BMPs (i.e. pharmacological level) in clinical settings required to substantially induce a bone formation, concurrent with potential unexpected side effects (i.e. bone resorption, inflammation) presumably due to a broader population of cell-types exposed to the high-dose BMPs rather than osteoblastic lineage cells.
journal_name
Bonejournal_title
Boneauthors
Kamiya N,Atsawasuwan P,Joiner DM,Waldorff EI,Goldstein S,Yamauchi M,Mishina Ydoi
10.1016/j.bone.2020.115513subject
Has Abstractpub_date
2020-09-01 00:00:00pages
115513eissn
8756-3282issn
1873-2763pii
S8756-3282(20)30293-3journal_volume
138pub_type
杂志文章相关文献
BONE文献大全abstract::We investigated the function of Ca2+ in the activation of phosphatidylcholine (PC)-hydrolyzing phospholipase D (PLD) in osteoblast-like MC3T3-E1 cells. Fetal calf serum (FCS) stimulated the formation of choline in a dose-dependent manner in the range between 0.6% and 10%. The effect of a combination of FCS and 12-O-te...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/s8756-3282(96)00185-8
更新日期:1996-10-01 00:00:00
abstract::The loss of trabecular bone in the ovariectomized (OVX) rat provides a useful experimental model of postmenopausal osteoporosis. In this study, two bone-modulating compounds, an NSAID (flurbiprofen: FBP) and a chemically modified nonantimicrobial tetracycline (CMT), were tested either individually or in combination in...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/s8756-3282(96)00280-3
更新日期:1996-12-01 00:00:00
abstract::Bone sialoprotein (BSP) is a multifunctional extracellular matrix protein found in mineralized tissues, including bone, cartilage, tooth root cementum (both acellular and cellular types), and dentin. In order to define the role BSP plays in the process of biomineralization of these tissues, we analyzed cementogenesis,...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/j.bone.2015.05.007
更新日期:2015-09-01 00:00:00
abstract::Trauma-induced heterotopic ossification is an intriguing phenomenon involving the inappropriate ossification of soft tissues within the body such as the muscle and ligaments. This inappropriate formation of bone is highly prevalent in those affected by blast injuries. Here, we developed a simplified cell culture model...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/j.bone.2018.09.008
更新日期:2018-12-01 00:00:00
abstract::The assessment of fracture risk often relies primarily on measuring bone mineral density, thereby accounting for only a single pathology: the loss of bone mass. However, bone's ability to resist fracture is a result of its biphasic composition and hierarchical structure that imbue it with high strength and toughness. ...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/j.bone.2016.03.013
更新日期:2016-06-01 00:00:00
abstract::Juvenile osteoporosis (JO) is characterized by bone fragility during development, low bone mass and absence of extraskeletal features. Heterozygous loss-of-function mutations in LRP5 have been found in a few patients, but bone tissue and bone material abnormalities associated with such mutations have not been determin...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/j.bone.2013.07.020
更新日期:2013-11-01 00:00:00
abstract::Microdeletions within 1q24 have been associated with growth deficiency, varying intellectual disability, and skeletal abnormalities. The candidate locus responsible for the various phenotypic features of this syndrome has previously been predicted to lie in the area of 1q24.3, but molecular evidence of the causative g...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/j.bone.2020.115705
更新日期:2021-01-01 00:00:00
abstract::The potency of magnetic resonance imaging (MRI) to measure the exact extent of osteonecrosis of the femoral head (ONFH) remains uncertain. The objective of this study was to determine if the volume of necrosis assessed with MRI accurately reflects the volume of architectural mineral alterations in osteonecrosis of the...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/j.bone.2019.115099
更新日期:2020-01-01 00:00:00
abstract::Previous reports have shown that bone mass and architecture will partially recover by remobilization (RM) in immobilization (IM)-induced osteopenia. The aim of this study was to test whether PTH can accelerate the recovery during RM from the IM-induced osteopenia. Six-month-old Sprague-Dawley female rats were divided ...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/8756-3282(95)00295-o
更新日期:1995-10-01 00:00:00
abstract::Oestrogen deficiency-related bone loss in the ovariectomized (OVX) mouse is a common model for osteoporosis. However, a comprehensive in vivo assessment of intervention-related changes in multiple bone properties, and in multiple mouse strains, is required in order to identify an appropriate model for future evaluatio...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/j.bone.2019.06.024
更新日期:2019-10-01 00:00:00
abstract::This study is designed to test how intermittent application of prostaglandin E2 (PGE2) and risedronate (Ris) alone or in combination acts on the cancellous bone mass in estrogen-deficient rats. Sprague-Dawley rats were ovariectomized (ovx) or sham-ovx'd at 6 months of age. PGE2 (6mg/kg/d), Ris (5 micrograms/kg/twice a...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/8756-3282(95)00305-w
更新日期:1995-10-01 00:00:00
abstract::We believe that the assembled data are consistent with the presence of mRNA species and/or proteins in pagetic bone that are recognized by some paramyxovirus antibodies and nucleic acid probes. The evidence presented so far is insufficient to substantiate claims for the "unequivocal" presence of paramyxovirus sequence...
journal_title:Bone
pub_type: 杂志文章,评审
doi:10.1016/s8756-3282(99)00032-0
更新日期:1999-05-01 00:00:00
abstract::Previously we observed that capsaicin treatment in rats inhibited sensory neuropeptide signaling, with a concurrent reduction in trabecular bone formation and bone volume, and an increase in osteoclast numbers and bone resorption. Calcitonin-gene-related peptide (CGRP) is a neuropeptide richly distributed in sensory n...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/j.bone.2009.11.029
更新日期:2010-05-01 00:00:00
abstract::Hypophosphatasia (HPP) is caused by loss-of-function mutation(s) within the gene TNSALP that encodes the "tissue-nonspecific" isoenzyme of alkaline phosphatase (TNSALP). In HPP, inorganic pyrophosphate, an inhibitor of mineralization and substrate for TNSALP, accumulates extracellularly often leading to rickets or ost...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/j.bone.2015.02.022
更新日期:2015-06-01 00:00:00
abstract::We have tested the ability of the XCT960A to detect bone loss in OVX-rats, as well as bone gain in the proximal tibial metaphysis of healthy rats treated with hPTH(1-34). The results demonstrated that high precision can be achieved, with CV's for most measurement parameters in the range of 1.6 to 5.9% being obtained i...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/8756-3282(95)00287-n
更新日期:1995-10-01 00:00:00
abstract::The neuropeptide Y system has emerged as one of the major neural signalling pathways regulating bone homeostasis. Absence of Y1 receptor signalling from bone forming osteoblasts is responsible for an enhancement on bone mass in mice, suggesting that pharmacological blockade of Y1 receptors may offer a novel anabolic t...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/j.bone.2012.03.020
更新日期:2012-07-01 00:00:00
abstract::Osteosarcoma is a highly metastatic tumor affecting adolescents, for which there is no second-line chemotherapy. As suggested for most tumors, its capability to overgrow is probably driven by cancer stem cells (CSCs), and finding new targets to kill CSCs may be critical for improving patient survival. TP53 is the most...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/j.bone.2013.12.021
更新日期:2014-03-01 00:00:00
abstract::Liver X receptors (LXRs) are nuclear receptors that play a crucial role in the transcriptional control of lipid metabolism. Pharmacological LXR activation is an attractive concept for the treatment of atherosclerosis. Genetic LXR deficiency in mice has been shown to have an effect on bone turnover and structure and LX...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/j.bone.2010.08.018
更新日期:2011-02-01 00:00:00
abstract::The gap junction protein, connexin43 (Cx43) controls both bone formation and osteoclastogenesis via osteoblasts and/or osteocytes. Cx43 has also been proposed to mediate an anti-apoptotic effect of bisphosphonates, potent inhibitors of bone resorption. We studied whether bisphosphonates are effective in protecting mic...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/j.bone.2012.06.018
更新日期:2012-10-01 00:00:00
abstract::Human vertebral cancellous bone from white males (N = 19), black males (N = 16), white females (N = 12), and black females (N = 17) was examined histologically for the presence, numerical density, and morphology of in vivo microscopic cracking (microdamage). Two patterns of microcracks, linear and cross-hatched, were ...
journal_title:Bone
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1016/8756-3282(96)88871-5
更新日期:1996-08-01 00:00:00
abstract::The long-term protective effect of stronger back muscles on the spine was determined in 50 healthy white postmenopausal women, aged 58-75 years, 8 years after they had completed a 2 year randomized, controlled trial. Twenty-seven subjects had performed progressive, resistive back-strengthening exercises for 2 years an...
journal_title:Bone
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1016/s8756-3282(02)00739-1
更新日期:2002-06-01 00:00:00
abstract:BACKGROUND:The treatment of complex bone loss scenarios remains challenging. This study evaluates the efficacy of ex vivo regional gene therapy using transduced human adipose-derived stem cells (ASCs) overexpressing bone morphogenetic protein-2 (BMP-2) to treat critical-sized bone defects. METHODS:Critical-sized femor...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/j.bone.2020.115524
更新日期:2020-09-01 00:00:00
abstract::Fracture risk and mechanical competence of bone are functions of bone mass and tissue quality, which in turn are dependent on the bone's mechanical environment. Male mice have a greater response to non-weight-bearing exercise than females, resulting in larger, stronger bones compared with control animals. The aim of t...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/j.bone.2006.12.002
更新日期:2007-04-01 00:00:00
abstract:BACKGROUND:NF-κB essential modulator (NEMO), encoded by IKBKG, is necessary for activation of the ubiquitous transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Animal studies suggest NEMO is required for NF-κB mediated bone homeostasis, but this has not been thoroughly studied ...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/j.bone.2019.01.014
更新日期:2019-04-01 00:00:00
abstract::A theory is developed to resolve several inconsistencies between current concepts and observations about bone remodeling. For example, the observation that remodeling increases both when mechanical loading is excessively low, that is, in a disuse state, and when it is excessively high, producing substantial fatigue da...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/s8756-3282(99)00241-0
更新日期:2000-01-01 00:00:00
abstract::The aim of the study was to assess the biomechanical effects of short-term PTH treatment and withdrawal on bone mass and strength in an aged, osteopenic, ovariectomized (ovx) rat model. Additionally, the effect of sequential therapy with PTH and the bisphosphonate, risedronate, the effect of longterm PTH monotherapy, ...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/s8756-3282(97)00024-0
更新日期:1997-05-01 00:00:00
abstract::Five strains of inbred mice were found to have variations in bone mass although they were similar in body weight. Two of these strains, C57BL/6J and A/J, were studied in greater detail and the former had more bone in both femur and tibia. The increased bone mass was associated with larger quadriceps muscles in the C57...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/s8756-3282(00)00164-2
更新日期:1995-08-01 00:00:00
abstract::It has been established during the past few years that interleukin(s)-1, -6, -11 (IL-1, IL-6, IL-11), and tumor necrosis factor (TNF) can stimulate osteoclast development and thereby the process of bone resorption. Moreover, upregulation of the production and/or action of IL-6 has been implicated in the pathogenesis o...
journal_title:Bone
pub_type: 杂志文章,评审
doi:10.1016/8756-3282(95)00180-l
更新日期:1995-08-01 00:00:00
abstract::The ovariectomized (OVX) rat is a well established model for osteoporosis research. The recent development of in vivo micro-computed tomography (micro-CT) provides new possibilities to monitor individual bone changes over time. The purpose of this study was to establish the normal time course of bone loss in the OVX r...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/j.bone.2006.04.017
更新日期:2006-10-01 00:00:00
abstract::Eldecalcitol (ELD), an active form of vitamin D analog approved for the treatment of osteoporosis in Japan, increases lumbar spine bone mineral density (BMD), suppresses bone turnover markers, and reduces fracture risk in patients with osteoporosis. We have previously reported that treatment with ELD for 6 months impr...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/j.bone.2014.11.025
更新日期:2015-04-01 00:00:00