Phlpp phosphatases in osteoarthritis
Phlpp phosphatases in osteoarthritis
批准号:
10707868
负责人:
Jennifer J Westendorf
金额:
$39.75万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-09-21 至 2027-08-31
关键词:
AdultAffectAfferent NeuronsAgeAge MonthsAgingAnimal ModelArthralgiaArticulationAtomic Force MicroscopyBehaviorBehavior TherapyBiological AssayBiomechanicsBone SpurCartilageCell ProliferationCellsChondrocytesCompensationCoupledDataDegenerative polyarthritisDeteriorationDevelopmentDiseaseDisease ProgressionEconomic BurdenElasticityEnzymesGenesGoalsHistologyHistopathologyHumanIn VitroInjuryIntra-Articular InjectionsJointsKnock-outKnockout MiceMeasuresMedial meniscus structureMeniscus structure of jointMessenger RNAMolecularMotionMusNatural regenerationNeuritesNeuronal PlasticityNeuronsNeurotransmittersOperative Surgical ProceduresPainPainlessPathogenesisPathologicPathologyPeriosteumPharmaceutical PreparationsPhenotypePhosphoric Monoester HydrolasesProductionProliferatingPropertyReporterRisk FactorsRoleSalineSurfaceSynovial MembraneSynovitisTamoxifenTestingThickTissuesWeight-Bearing stateWorkaggrecanallodyniaarticular cartilageburden of illnesscartilage degradationcartilage regenerationcartilage repaircell typechronic painful conditiondisabilityimproved mobilityin vivoinhibitorinnovationinsightinterestjoint injuryligament injurymultidisciplinarynerve supplyneurofilamentnovel therapeuticsosteoarthritis painoverexpressionpain behaviorpain reliefpalliativepreservationpreventregenerativesmall molecule inhibitorsubchondral bonetissue regenerationtissue repairtranscriptomics
中文摘要
摘要
骨关节炎(OA)是一种慢性疼痛性疾病,也是世界各地残疾的主要原因。OA是
其特征在于关节软骨退化和其他关节病变,包括半月板和韧带
损伤、滑膜炎、骨刺和关节疼痛。目前批准的治疗方法都不能改变疾病
通过减缓关节软骨退化或修复关节组织损伤来改善关节炎的进展。我们确认了菲利普的身份
磷酸酶作为软骨再生和关节疼痛的可修饰靶点。Phlpp 1和Phlpp 2是
在人OA软骨中异常表达。Phlpp 1敲除(KO)小鼠免受软骨损伤
退化和疼痛相关的行为(异常性疼痛和活动减少)手术后,不稳定的
内侧半月板(DMM),但Phlpp 1在仅表达聚集蛋白聚糖(Agc)的小鼠中条件性缺失
细胞(Phlpp 1 CKOAgc)仅被保护免于软骨降解,而不降低移动性。这些结果
表明Phlpp 1在软骨细胞中内在作用,以及Phlpp 1/2在其它组织或细胞中的作用
在铰接关节内。有趣的是,Phlpp 1和Phlpp 2的小分子抑制剂进一步减缓软骨
在Phlpp 1 CKOAgc小鼠中降解并增加移动性。Phlpp 1/2抑制剂也刺激软骨细胞
增殖和基质的产生,并阻止神经突生长和感觉神经元基因的表达,
体外和体内。总之,这些数据表明,体内多种细胞类型/组织中的Phlpp 1/2活性
关节连接关节有助于OA发病机制,Phlpp 2可能通过以下方式促进OA表型:
补偿软骨中Phlpp 1的缺乏和/或通过调节关节神经支配和疼痛相关的
行为。本项目的总体目标是确定Phlpp 1和Phlpp 2如何调节软骨数量
和质量(即硬度)以及Phlpp 1/2失活如何有助于损伤诱导的神经支配。具体
目的是:1)阐明Phlpp 1和Phlpp 2在关节损伤后关节软骨细胞中的作用,2)
确定Phlpp 1和Phlpp 2如何影响关节软骨的生物力学和结构特性,
损伤后和整个衰老过程中的其他关节组织,以及3)确定感觉神经元中Phlpp 1/2的活性
和OA相关的疼痛行为。这些研究将提供关于以下关系的新信息:
关节损伤、关节神经支配和疼痛。这种见解将使急需的疾病的发展-
治疗骨关节炎的药物
英文摘要
ABSTRACT
Osteoarthritis (OA) is a chronically painful condition and a leading cause of disability around the world. OA is
characterized by articular cartilage deterioration and other joint pathologies including meniscus and ligament
damage, synovitis, bone spurs and joint pain. None of the currently approved treatments alter disease
progression by slowing articular cartilage degradation or repairing damage to joint tissues. We identified Phlpp
phosphatases as modifiable targets for cartilage regeneration and joint pain. Phlpp1 and Phlpp2 are
abnormally expressed in human OA cartilage. Phlpp1 knockout (KO) mice are protected from cartilage
degradation and pain-related behaviors (allodynia and reduced mobility) after surgery that destabilizes the
medial meniscus (DMM), but mice where Phlpp1 is conditionally depleted in just aggrecan (Agc)-expressing
cells (Phlpp1 CKOAgc) are only protected from cartilage degradation, not reduced mobility. These results
indicate an intrinsic role for Phlpp1 in chondrocytes, as well as a role for Phlpp1/2 in other tissues or cells
within articulating joints. Of interest, small molecule inhibitors of Phlpp1 and Phlpp2 further slow cartilage
degradation in Phlpp1 CKOAgc mice and increase mobility. Phlpp1/2 inhibitors also stimulate chondrocyte
proliferation and matrix production and prevent neurite outgrowth and expression of sensory neuron genes in
vitro and in vivo. Together these data indicate that Phlpp1/2 activity in multiple cell types/tissues within
articulating joints contributes to OA pathogenesis and that Phlpp2 may contribute to OA phenotypes by
compensating for Phlpp1 deficiency in cartilage and/or by regulating joint innervation and pain-related
behaviors. The overall goals of this project are to define how Phlpp1 and Phlpp2 modulate cartilage quantity
and quality (i.e. stiffness) and how Phlpp1/2 inactivation contributes to injury-induced innervation. The specific
aims are to: 1) Elucidate the roles of Phlpp1 and Phlpp2 in articular chondrocytes following a joint injury, 2)
Determine how Phlpp1 and Phlpp2 affect biomechanical and structural properties of articular cartilage and
other joint tissues after injury and throughout aging, and 3) Define activities of Phlpp1/2 in sensory neurons
and OA-associated pain behaviors. These studies will provide new information about the relationship between
joint damage, joint innervation and pain. Such insights will enable the development of much needed disease-
modifying drugs for osteoarthritis.
期刊论文(1)
专著(0)
科研奖励(0)
会议论文
DOI:
10.3390/s23041835
发表时间:
2023-02-07
期刊:
Sensors (Basel, Switzerland)
影响因子:
--
作者:
[Arnold KM, Sicard D, Tschumperlin DJ, Westendorf JJ]
通讯作者:
Westendorf JJ
Phlpp phosphatases in osteoarthritis
-
批准号:10318360
-
项目类别:
-
资助金额:$39.75万
-
财政年份:2022
-
负责人:Jennifer J Westendorf
-
依托单位:
Girk2/3 channels in cartilage biology and disease
-
批准号:9902333
-
项目类别:
-
资助金额:$17.49万
-
财政年份:2019
-
负责人:Jennifer J Westendorf
-
依托单位:
Girk2/3 channels in cartilage biology and disease
-
批准号:9755834
-
项目类别:
-
资助金额:$20.99万
-
财政年份:2019
-
负责人:Jennifer J Westendorf
-
依托单位:
Protein Phosphatase Phlpp1 in Cartilage Development & Osteoarthritis Progression
-
批准号:9316518
-
项目类别:
-
资助金额:$34.98万
-
财政年份:2014
-
负责人:Jennifer J Westendorf
-
依托单位:
Phlpp protein phosphatases in cartilage development and disease
-
批准号:10021149
-
项目类别:
-
资助金额:$55.18万
-
财政年份:2014
-
负责人:Jennifer J Westendorf
-
依托单位:
Protein Phosphatase Phlpp1 in Cartilage Development & Osteoarthritis Progression
-
批准号:8687230
-
项目类别:
-
资助金额:$34.98万
-
财政年份:2014
-
负责人:Jennifer J Westendorf
-
依托单位:
Runx2 and Axin2 Interactions During Bone Formation
-
批准号:8092653
-
项目类别:
-
资助金额:$37.1万
-
财政年份:2010
-
负责人:Jennifer J Westendorf
-
依托单位:
Runx2 and Axin2 Interactions During Bone Formation
-
批准号:8721570
-
项目类别:
-
资助金额:$9.62万
-
财政年份:2010
-
负责人:Jennifer J Westendorf
-
依托单位:
Runx2 and Axin2 Interactions During Bone Formation
-
批准号:8685767
-
项目类别:
-
资助金额:$47.48万
-
财政年份:2010
-
负责人:Jennifer J Westendorf
-
依托单位:
Runx2 and Axin2 Interactions During Bone Formation
-
批准号:8485581
-
项目类别:
-
资助金额:$36.35万
-
财政年份:2010
-
负责人:Jennifer J Westendorf
-
依托单位:
Runx2 and Axin2 Interactions During Bone Formation
-
批准号:8277079
-
项目类别:
-
资助金额:$37.86万
-
财政年份:2010
-
负责人:Jennifer J Westendorf
-
依托单位:
Musculoskeletal Research Training Program
-
批准号:8261861
-
项目类别:
-
资助金额:$33.91万
-
财政年份:2009
-
负责人:Jennifer J Westendorf
-
依托单位:
Musculoskeletal Research Training Program
-
批准号:7822860
-
项目类别:
-
资助金额:$31.85万
-
财政年份:2009
-
负责人:Jennifer J Westendorf
-
依托单位:
Regulation of RUNX-2 Transcriptional Activity
-
批准号:7900638
-
项目类别:
-
资助金额:$7.14万
-
财政年份:2009
-
负责人:Jennifer J Westendorf
-
依托单位:
Musculoskeletal Research Training Program
-
批准号:8664128
-
项目类别:
-
资助金额:$26.67万
-
财政年份:2009
-
负责人:Jennifer J Westendorf
-
依托单位:
Musculoskeletal Research Training Program
-
批准号:10403945
-
项目类别:
-
资助金额:$56.63万
-
财政年份:2009
-
负责人:Jennifer J Westendorf
-
依托单位:
Musculoskeletal Research Training Program
-
批准号:10615206
-
项目类别:
-
资助金额:$39.02万
-
财政年份:2009
-
负责人:Jennifer J Westendorf
-
依托单位:
Musculoskeletal Research Training Program
-
批准号:7626157
-
项目类别:
-
资助金额:$32.64万
-
财政年份:2009
-
负责人:Jennifer J Westendorf
-
依托单位:
Musculoskeletal Research Training Program
-
批准号:9914218
-
项目类别:
-
资助金额:$47.73万
-
财政年份:2009
-
负责人:Jennifer J Westendorf
-
依托单位:
Musculoskeletal Research Training Program
-
批准号:8465098
-
项目类别:
-
资助金额:$30.49万
-
财政年份:2009
-
负责人:Jennifer J Westendorf
-
依托单位:
海外基金