Abstract:
:Heterotopic ossification (HO) involves formation of endochondral bone at non-skeletal sites, is prevalent in severely wounded service members, and causes significant complications and delayed rehabilitation. As common prophylactic treatments such as anti-inflammatory drugs and irradiation cannot be used after multi-system combat trauma, there is an urgent need for new remedies. Previously, we showed that the retinoic acid receptor γ agonist Palovarotene inhibited subcutaneous and intramuscular HO in mice, but those models do not mimic complex combat injury. Thus, we tested Palovarotene in our validated rat trauma-induced HO model that involves blast-related limb injury, femoral fracture, quadriceps crush injury, amputation and infection with methicillin-resistant Staphylococcus aureus from combat wound infections. Palovarotene was given orally for 14days at 1mg/kg/day starting on post-operative day (POD) 1 or POD-5, and HO amount, wound dehiscence and related processes were monitored for up to 84days post injury. Compared to vehicle-control animals, Palovarotene significantly decreased HO by 50 to 60% regardless of when the treatment started and if infection was present. Histological analyses showed that Palovarotene reduced ectopic chondrogenesis, osteogenesis and angiogenesis forming at the injury site over time, while fibrotic tissue was often present in place of ectopic bone. Custom gene array data verified that while expression of key chondrogenic and osteogenic genes was decreased within soft tissues of residual limb in Palovarotene-treated rats, expression of cartilage catabolic genes was increased, including matrix metalloproteinase-9. Importantly, Palovarotene seemed to exert moderate inhibitory effects on wound healing, raising potential safety concerns related to dosing and timing. Our data show for the first time that Palovarotene significantly inhibits HO triggered by blast injury and associated complications, strongly indicating that it may prevent HO in patients at high risk such as those sustaining combat injuries and other forms of blast trauma.
journal_name
Bonejournal_title
Boneauthors
Pavey GJ,Qureshi AT,Tomasino AM,Honnold CL,Bishop DK,Agarwal S,Loder S,Levi B,Pacifici M,Iwamoto M,Potter BK,Davis TA,Forsberg JAdoi
10.1016/j.bone.2016.06.014subject
Has Abstractpub_date
2016-09-01 00:00:00pages
159-67eissn
8756-3282issn
1873-2763pii
S8756-3282(16)30176-4journal_volume
90pub_type
杂志文章相关文献
BONE文献大全abstract::Chondrocyte proliferation and differentiation are crucial for endochondral ossification and strictly regulated by numerous signaling molecules and transcription factors, but the hierarchical regulatory network remains to be deciphered. The present study emphasized the interplay of Activin A, Foxa, Notch and Shh signal...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/j.bone.2019.03.036
更新日期:2019-06-01 00:00:00
abstract::Nearly all bone fractures in humans can deteriorate into a non-union fracture, often due to formation of fibrotic tissue. Cranial allogeneic bone grafts present a striking example: although seemingly attractive for craniofacial reconstructions, they often fail due to fibrosis at the host-graft junction, which physical...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/j.bone.2017.01.020
更新日期:2017-04-01 00:00:00
abstract::How estrogen therapy influences bone metabolism in postmenopausal women has previously been studied using several approaches, including bone densitometry, measurement of biochemical markers of bone turnover, and histomorphometry. Taken together, these investigations suggest that conventional doses of estrogen protect ...
journal_title:Bone
pub_type: 杂志文章,评审
doi:10.1016/s8756-3282(98)00156-2
更新日期:1999-02-01 00:00:00
abstract:INTRODUCTION:The RANKL-OPG axis is a key regulator of osteoclastogenesis and bone turnover activity. Its contribution to bone resorption under altered mechanical states, however, has not been fully elucidated. Here we examined the role of OPG in regulating mechanically induced bone modeling in a rat model of orthodonti...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/j.bone.2007.04.194
更新日期:2007-09-01 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::Ecto-nucleotide pyrophosphatase/phosphodiesterases (NPPs) hydrolyse nucleotide triphosphates to the corresponding nucleotide monophosphates and the mineralisation inhibitor, pyrophosphate (PPi). This study examined the role of NPP1 in osteocytes, osteoclasts and cortical bone, using a mouse model lacking NPP1 (Enpp1(-...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/j.bone.2014.09.016
更新日期:2014-12-01 00:00:00
abstract:INTRODUCTION:While the anti-resorptive effects of the bisphosphonates (BPs) are well documented, many questions remain about their mechanisms of action, particularly following long-term use. This study evaluated the effects of alendronate (Ale) treatment on TGF-β1 signaling in mesenchymal stem cells (MSCs) and osteocyt...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/j.bone.2012.10.017
更新日期:2013-01-01 00:00:00
abstract::This cohort study of postmenopausal women in the United Kingdom aged ≥50years determined the incremental cost of health care and clinical outcomes in the 12months following incident, selected fractures (non-vertebral non-hip [NVNHF], vertebral [VF] and multiple [MF]). Incremental costs and outcomes of the fracture coh...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/j.bone.2012.05.020
更新日期:2012-09-01 00:00:00
abstract::Low-intensity pulsed ultrasound (LIPUS) has been used to accelerate bone fracture healing. However, the issue whether LIPUS is effective in preventing osteoporosis has not been clarified, and if so, what possible mechanisms might be responsible. Myostatin (MSTN) is a negative regulator of muscle growth, and its absenc...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/j.bone.2020.115610
更新日期:2021-02-01 00:00:00
abstract::Pseudoachondroplasia (PSACH), a severe short-limbed dwarfing condition, is associated with life-long joint pain and early onset osteoarthritis. PSACH is caused by mutations in cartilage oligomeric matrix protein (COMP), a pentameric matricellular protein expressed primarily in cartilage and other musculoskeletal tissu...
journal_title:Bone
pub_type: 杂志文章,评审
doi:10.1016/j.bone.2017.03.045
更新日期:2017-09-01 00:00:00
abstract::The use of combined antiretroviral agents during pregnancy is important to prevent mother-to-child transmission of human immunodeficiency virus (HIV). Antiretroviral treatment (ARV) is associated with reduced bone mass and altered bone metabolism in HIV-infected patients. There are no data regarding the effect of ARV ...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/j.bone.2011.10.030
更新日期:2012-01-01 00:00:00
abstract::If muscle force is a primary source for triggering bone adaptation, with disuse and reloading, bone changes should follow muscle changes. We examined the timing and magnitude of changes in muscle cross-sectional area (MCSA) and bone architecture in response to muscle inactivity following botulinum toxin (BTX) injectio...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/j.bone.2009.10.016
更新日期:2010-01-01 00:00:00
abstract::Active vitamin D is a major therapeutic agent for bone disease. Although some studies have reported that vitamin D ameliorates bone disease related to diabetes, the mechanism remains unclear. Our study investigated the effect of the vitamin D receptor activator 22-oxacalcitriol (OCT) on bone disease in a rat model of ...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/j.bone.2015.01.014
更新日期:2015-05-01 00:00:00
abstract::Due to the reduction in bone mass and deterioration in bone microarchitecture, osteoporosis is an important risk factor for impairing implant osseointegration. Recently, low-magnitude, high-frequency (LMHF) vibration (LM: <1×g; HF: 20-90Hz) has been shown to exhibit anabolic, but anti-resorptive effects on skeletal ho...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/j.bone.2014.09.026
更新日期:2015-02-01 00:00:00
abstract::Regulation of calcium release from mouse calvariae by glycosaminoglycans and known modulators of bone resorption has been examined. Anticoagulant and nonanticoagulant fragments of heparin were combined with parathyroid hormone (PTH) and interleukin-1, beta (IL1), and calcium release from radiolabeled bone was determin...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/8756-3282(88)90018-x
更新日期:1988-01-01 00:00:00
abstract::Osteoporosis is the consequence of altered bone metabolism resulting in the systemic reduction of bone strength and increased risk of fragility fractures. MicroRNAs (miRNAs) regulate gene expression on a post-transcriptional level and are known to take part in the control of bone formation and bone resorption. In addi...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/j.bone.2015.05.027
更新日期:2015-10-01 00:00:00
abstract::We investigated the effect of 2-beta-(3-hydroxypropoxy)-1alpha,25-dihydroxyvitamin D3 (ED-71) on the modeling of bone in distraction osteogenesis. The tibiae of 30 rabbits were lengthened by 10 mm in 10 days. Following osteotomy, ED-71 (0.05 microg/kg) was administered subcutaneously twice a week to the ED-71 group un...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/s8756-3282(98)00179-3
更新日期:1999-03-01 00:00:00
abstract::Interleukin-1 (IL-1) has been shown to promote osteoclast (OC) differentiation, in addition to acting as a survival factor for mature osteoclasts. In this study, we investigate the expression of IL-1 during human osteoclast formation, taking advantage of a recently reported in vitro culture system that generates human...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/s8756-3282(99)00176-3
更新日期:1999-09-01 00:00:00
abstract::Recent studies have indicated a critical role for vascular endothelial growth factor (VEGF) during the process of endochondral ossification, in particular in coupling cartilage resorption with bone formation. Therefore, we studied the chemoattractive and proliferative properties of human VEGF-A on primary human osteob...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/s8756-3282(01)00690-1
更新日期:2002-03-01 00:00:00
abstract::Bone loss represents a major unsolved problem in rheumatoid arthritis (RA). The skeletal complications of RA consist of focal bone erosions and periarticular osteoporosis at sites of active inflammation, and generalized bone loss with reduced bone mass. New evidence indicates that osteoclasts are key mediators of all ...
journal_title:Bone
pub_type: 杂志文章,评审
doi:10.1016/s8756-3282(01)00682-2
更新日期:2002-02-01 00:00:00
abstract::It is well known that physical inactivity leads to loss of muscle mass, but it also causes bone loss. Mechanistically, osteoclastogenesis and bone resorption have recently been shown to be regulated by vibration. However, the underlying mechanism behind the inhibition of osteoclast formation is yet unknown. Therefore,...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/j.bone.2013.08.020
更新日期:2013-12-01 00:00:00
abstract::Amelogenin is the major enamel protein produced by ameloblasts. Its expression has been shown to be down-regulated in ameloblasts of vitamin-D-deficient (-D) rats. The potential expression and localization of amelogenin in odontoblasts and its regulation by vitamin D were investigated in this study. RT-PCR and semi-qu...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/s8756-3282(02)00978-x
更新日期:2003-03-01 00:00:00
abstract::One year of treatment with bisphosphonates at 5x the dose used for post-menopausal osteoporosis significantly increases failure load and microdamage, and decreases toughness at multiple skeletal sites in intact female beagles. The goal of this study was to determine if similar changes occur with doses equivalent to th...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/j.bone.2006.04.028
更新日期:2006-10-01 00:00:00
abstract::Bisphosphonates are widely used to treat children with osteogenesis imperfecta (OI), a bone fragility disorder that is most often caused by mutations in COL1A1 or COL1A2. However, it is unclear whether this treatment decreases the risk of developing scoliosis. We retrospectively evaluated spine radiographs and charts ...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/j.bone.2016.02.018
更新日期:2016-05-01 00:00:00
abstract::A stabilized tibia fracture model was used in young (8-week old) and aged (1-year old) mice to define the relative bone regenerative potential and the relative responsiveness of the periosteal progenitor population with aging and PTH 1-34 (PTH) systemic therapy. Bone regeneration was assessed through gene expressions,...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/j.bone.2014.02.002
更新日期:2014-05-01 00:00:00
abstract::Mutations in the GALNT3 gene result in familial tumoral calcinosis, characterized by persistent hyperphosphatemia and ectopic calcific masses in soft tissues. Since calcific masses often recur after surgical removal, a more permanent solution to the problem is required. Nicotinamide is reported to lower serum phosphat...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/j.bone.2014.06.036
更新日期:2014-10-01 00:00:00
abstract::To examine the ability of tamoxifen (TAM) to conserve bone in the estrogen-deficient ovariectomized (OVX) rat in the presence and absence of parathyroid hormone (PTH) six groups of rats with 45Ca-labeled bones were studied for 12 weeks. Rats were OVX, parathyroidectomized (PTX), or given sham operations and treated wi...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/8756-3282(94)90273-9
更新日期:1994-09-01 00:00:00
abstract::Biochemical bone turnover markers (BTMs) provide important information on the diagnosis, therapy and monitoring of metabolic bone diseases including osteoporosis. One goal of antiresorptive therapy in women is to decrease biochemical BTMs to the lower half of reference intervals for healthy pre-menopausal counterparts...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/j.bone.2010.07.017
更新日期:2010-10-01 00:00:00
abstract::Patients with coxarthrosis (cOA) have a reduced incidence of intracapsular femoral neck fracture, suggesting that cOA offers protection. The distribution of bone in the femoral neck was compared in cases of coxarthrosis and postmortem controls to assess the possibility that disease-associated changes might contribute ...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/s8756-3282(02)00920-1
更新日期:2003-01-01 00:00:00
abstract::The process of bone turnover displays variations over 24 h, with C-terminal cross-linked telopeptide of type 1 collagen (CTX) and osteocalcin exhibiting a nadir in the afternoon and a peak in the night. In contrast, N-terminal propeptide of type 1 procollagen (P1NP) did not display an apparent 24-hour rhythm. Other em...
journal_title:Bone
pub_type: 杂志文章
doi:10.1016/j.bone.2018.10.002
更新日期:2019-03-01 00:00:00