Limb- and tendon-specific Adamtsl2 deletion identifies a role for ADAMTSL2 in tendon growth in a mouse model for geleophysic dysplasia

Hubmacher, Dirk; Taye, Nandaraj; Balic, Zerina; Thacker, Stetson; Adams, Sheila M.; Birk, David E.; Schweitzer, Ronen

doi:10.1016/j.matbio.2019.02.001

Cited by 22 publications

(31 citation statements)

References 61 publications

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“…148,149 We recently described a role for ADAMTSL2 in modulating the composition of the PCM around tenocytes in the Achilles tendon. 150 Specifically, we found increased FBN1 deposition in the absence of ADAMTSL2. Remarkably, tenocyte organization in linear arrays was distorted and Achilles tendons were shorter and wider.…”

Section: Fibrillins and Elastinmentioning

confidence: 61%

“…Fbn2 knockout mice showed temporary forelimb contractures and decreased collagen fibril cross‐linking in the digital flexor tendons . We recently described a role for ADAMTSL2 in modulating the composition of the PCM around tenocytes in the Achilles tendon . Specifically, we found increased FBN1 deposition in the absence of ADAMTSL2.…”

Section: The Pcm Of Tendon‐resident Cellsmentioning

confidence: 67%

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The “other” 15–40%: The Role of Non‐Collagenous Extracellular Matrix Proteins and Minor Collagens in Tendon

Taye

Karoulias

Hubmacher

2019

Journal Orthopaedic Research

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Extracellular matrix (ECM) determines the physiological function of all tissues, including musculoskeletal tissues. In tendon, ECM provides overall tissue architecture, which is tailored to match the biomechanical requirements of their physiological function, that is, force transmission from muscle to bone. Tendon ECM also constitutes the microenvironment that allows tendon‐resident cells to maintain their phenotype and that transmits biomechanical forces from the macro‐level to the micro‐level. The structure and function of adult tendons is largely determined by the hierarchical organization of collagen type I fibrils. However, non‐collagenous ECM proteins such as small leucine‐rich proteoglycans (SLRPs), ADAMTS proteases, and cross‐linking enzymes play critical roles in collagen fibrillogenesis and guide the hierarchical bundling of collagen fibrils into tendon fascicles. Other non‐collagenous ECM proteins such as the less abundant collagens, fibrillins, or elastin, contribute to tendon formation or determine some of their biomechanical properties. The interfascicular matrix or endotenon and the outer layer of tendons, the epi‐ and paratenon, includes collagens and non‐collagenous ECM proteins, but their function is less well understood. The ECM proteins in the epi‐ and paratenon may provide the appropriate microenvironment to maintain the identity of distinct tendon cell populations that are thought to play a role during repair processes after injury. The aim of this review is to provide an overview of the role of non‐collagenous ECM proteins and less abundant collagens in tendon development and homeostasis. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:23–35, 2020

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Section: Fibrillins and Elastinmentioning

confidence: 61%

Section: The Pcm Of Tendon‐resident Cellsmentioning

confidence: 67%

The “other” 15–40%: The Role of Non‐Collagenous Extracellular Matrix Proteins and Minor Collagens in Tendon

Taye

Karoulias

Hubmacher

2019

Journal Orthopaedic Research

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“…We previously identified several TGF-β regulated genes for which expression is enriched in the putative IVD region of the embryonic sclerotome, including Adamtsl2, Fmod, and Scx 18,31,34 . Localization to a patterned subset of sclerotome was previously confirmed by in-situ hybridization 18,35 . Mutations in Adamtls2 result in a condition called Geleophysic dysplasia, which is characterized in part by short stature and joint contractures.…”

Section: Discussionmentioning

confidence: 78%

Canonical and noncanonical TGF-β signaling regulate fibrous tissue differentiation in the axial skeleton

Clayton

Ban

Liu

et al. 2020

Sci Rep

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Previously, we showed that embryonic deletion of TGF-β type 2 receptor in mouse sclerotome resulted in defects in fibrous connective tissues in the spine. Here we investigated how TGF-β regulates expression of fibrous markers: Scleraxis, Fibromodulin and Adamtsl2. We showed that TGF-β stimulated expression of Scleraxis mRNA by 2 h and Fibromodulin and Adamtsl2 mRNAs by 8 h of treatment. Regulation of Scleraxis by TGF-β did not require new protein synthesis; however, protein synthesis was required for expression of Fibromodulin and Adamtsl2 indicating the necessity of an intermediate. We subsequently showed Scleraxis was a potential intermediate for TGF-β-regulated expression of Fibromodulin and Adamtsl2. The canonical effector Smad3 was not necessary for TGF-β-mediated regulation of Scleraxis. Smad3 was necessary for regulation of Fibromodulin and Adamtsl2, but not sufficient to super-induce expression with TGF-β treatment. Next, the role of several noncanonical TGF-β pathways were tested. We found that ERK1/2 was activated by TGF-β and required to regulate expression of Scleraxis, Fibromodulin, and Adamtsl2. Based on these results, we propose a model in which TGF-β regulates Scleraxis via ERK1/2 and then Scleraxis and Smad3 cooperate to regulate Fibromodulin and Adamtsl2. These results define a novel signaling mechanism for TGFβ-mediated fibrous differentiation in sclerotome.

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“…ADAMTSL2 consists of a 30 amino acid signal peptide, an N-terminal thrombospondin type 1 repeat (TSR1), a cysteine rich-module, a peculiar spacer domain, an N-glycan-rich module, six tandem TSRs (TSR2-7), and a C-terminal PLAC (protease and lacunin) domain [7]. ADAMTSL2 binds fibrillin [4,8] but its role in microfibril assembly is not completely understood.Recent findings show that ADAMTSL2 specifically regulates in tendons microfibril assembly that is required for tendon growth [9].…”

Section: Introductionmentioning

confidence: 99%

Geleophysic dysplasia: novel missense variants and insights into ADAMTSL2 intracellular trafficking

Piccolo

Sabatino

Mithbaokar

et al. 2019

Molecular Genetics and Metabolism Reports

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Geleophysic dysplasia (GPHYSD1, MIM231050; GPHYSD2, MIM614185; GPHYSD3, MIM617809) is an autosomal disorder characterized by short-limb dwarfism, brachydactyly, cardiac valvular disease, and laryngotracheal stenosis. Mutations in ADAMTSL2 , FBN1 , and LTBP3 genes are responsible for this condition. We found that three previously described cases of GPHYSD diagnosed clinically were homozygote or compound heterozygotes for five ADAMTSL2 variants, four of which not being previously reported. By electron microscopy, skin fibroblasts available in one case homozygote for an ADAMTSL2 variant showed a defective intracellular localization of mutant ADAMTSL2 protein that did not accumulate within lysosome-like intra-cytoplasmic inclusions. Moreover, this mutant ADAMTSL2 protein was less secreted in medium and resulted in increased SMAD2 phosphorylation in transfected HEK293 cells.

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Limb- and tendon-specific Adamtsl2 deletion identifies a role for ADAMTSL2 in tendon growth in a mouse model for geleophysic dysplasia

Cited by 22 publications

References 61 publications

The “other” 15–40%: The Role of Non‐Collagenous Extracellular Matrix Proteins and Minor Collagens in Tendon

The “other” 15–40%: The Role of Non‐Collagenous Extracellular Matrix Proteins and Minor Collagens in Tendon

Canonical and noncanonical TGF-β signaling regulate fibrous tissue differentiation in the axial skeleton

Geleophysic dysplasia: novel missense variants and insights into ADAMTSL2 intracellular trafficking

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