Lysophosphatidic acid mediates fibrosis in injured joints by regulating collagen type I biosynthesis

Wu, Ling; Petrigliano, Frank A.; Ba, Kai; Lee, S.; Bogdanov, Jacob; McAllister, David R.; Adams, John S.; Rosenthal, Ann K.; Handel, Ben Van; Crooks, Gay M.; Lin, Yunfeng; Evseenko, Denis

doi:10.1016/j.joca.2014.11.012

Cited by 24 publications

(24 citation statements)

References 44 publications

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“…Metabolism and adipogenesis studies in mice indicate that ATX and its product, LPA, participate in energy homeostasis and obesity control ( 56-59, 104, 124, 125 ), which when dysregulated can lead to infl ammation and cancerogenesis. In addition to data showing association of ATX activity with rheumatoid arthritis ( 134 ), liver infl ammation ( 135,136 ), fi brosis development (137)(138)(139)(140)(141), and infl ammatory bowel disease ( 142 ), it has been proposed that ATX is mechanistically involved in linking both hepatitis C to hepatocellular carcinoma ( 143 ) and Epstein-Barr virus positivity to anaplastic large-cell and Hodgkin lymphoma development ( 107 ). MMTV-driven transgenic overexpression of either ATX or each of the three major LPA receptors (LPA1, -2, and -3) causes late-onset, invasive, and metastatic breast cancer development in mammary glands of mice ( 144 ).…”

Section: Role In Physiology and Cancer Pathophysiologymentioning

confidence: 99%

Thematic Review Series: Phospholipases: Central Role in Lipid Signaling and Disease Autotaxin, a lysophospholipase D with pleomorphic effects in oncogenesis and cancer progression

Federico

Jeong

Vellano

et al. 2016

Journal of Lipid Research

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a 125 kDa glycoprotein composed of 915 amino acids ( 1 ). Because it promoted chemotaxis on melanoma cells in an autocrine fashion, the protein was aptly named auto-taxin. Four years after the discovery of the fi rst variant, now commonly referred to as ATX ␣ , or melanoma ATX, a second isoform was cloned by the same team from the teratocarcinoma cell line, Ntera2D1. This polypeptide shared 94% identity with the melanoma protein and was immediately recognized as the alternatively spliced product of the same gene ( 2 ).The initial characterization of the fi rst isoform revealed that ATX biological activity was sensitive to pertussis toxin treatment. Furthermore, not only did the polypeptide share close homology with the murine pyrophosphatase/ type I phosphodiesterase (PDE) PC-1, including a threonine residue crucial for PDE enzymatic activity, but it was also able to hydrolyze PDE substrates in vitro ( 3 ). The confi rmation that ATX was an enzyme came when a new PDE, the PDE1/nucleotide pyrophosphatase (PD-1 ␣ /PDNP 2), was cloned from a cDNA library of human retina and found to be identical to the sequence of melanoma ATX ␣ with the exception of a missing stretch of 52 amino acids encoded by exon 12 in the central region of the open reading frame. The transcript of this variant, now frequently referred to as ATX ␤ , or teratoma ATX, produced a 863 amino acid polypeptide chain with a mass of 99,034 Da ( 4 ), and was independently isolated a few years later in mouse tissues ( 5 ). The third ATX isoform was detected for the fi rst time in rat brain, but was originally designated as PD-I ␣ , a brain-specifi c PDE I/nucleotide pyrophosphatase ( 6 ). Further research showed that PD-I ␣ was identical to ATX ␤ teratoma protein, except for the presence of an additional stretch of 25 amino acids encoded by an alternatively Abstract The ectonucleotide pyrophosphatase/phosphodiesterase type 2, more commonly known as autotaxin (ATX), is an ecto-lysophospholipase D encoded by the human ENNP2 gene. ATX is expressed in multiple tissues and participates in numerous key physiologic and pathologic processes, including neural development, obesity, infl ammation, and oncogenesis, through the generation of the bioactive lipid, lysophosphatidic acid. Overwhelming evidence indicates that altered ATX activity leads to oncogenesis and cancer progression through the modulation of multiple hallmarks of cancer pathobiology. Here, we review the structural and catalytic characteristics of the ectoenzyme, how its expression and maturation processes are regulated, and how the systemic integration of its pleomorphic effects on cells and tissues may contribute to cancer initiation, progression, and therapy. Additionally, the up-to-date spectrum of the most frequent ATX genomic alterations from The Cancer Genome Atlas project is reported for a subset of cancers. ( Fig. 1 ). In 1992, the fi rst alternatively spliced isoform was cloned from the melanoma cell line, A2058, and characterized as STRUCTURE AND ENZYMATIC ACTIVITY ATX belongs to the nuc...

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Section: Role In Physiology and Cancer Pathophysiologymentioning

confidence: 99%

Thematic Review Series: Phospholipases: Central Role in Lipid Signaling and Disease Autotaxin, a lysophospholipase D with pleomorphic effects in oncogenesis and cancer progression

Federico

Jeong

Vellano

et al. 2016

Journal of Lipid Research

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“…In addition to suppression of GLI2 by PFD, other anti-fibrotic drugs could target lysophosphatidic acid, which has also been shown to block collagen type 1 production by chondrocytes and stromal cells in vitro. 18 In conclusion, the chondroprotective potential of PFD shown in this cartilage injury model in young mice indicates that further studies of PFD's efficacy in older animals and with other models of OA are warranted. Cell and tissue specific effects of PFD should also be examined, in addition to investigation of the role that Has1 and hyaluronan metabolism may play in the joint injury response.…”

Section: Therapeutic Potential Of Pfd In Post-injury Musculoskeletal mentioning

confidence: 75%

“…PFD and other anti-fibrotic drugs 18 may also be able to supplement surgical and pharmaceutical interventions 63 , which individually have thus far been ineffective in preventing OA. Success rates of surgical interventions have shown arthroscopy to be ineffective in preventing OA 64 .…”

Section: Discussionmentioning

confidence: 99%

“…Naproxen, while effective in short-term pain treatment, may interfere with osteochondral repair in a mechanism involving enhanced expression of GLI2 57 , which is suppressed by the anti-fibrotic actions of PFD. In addition to suppression of GLI2 by PFD, other anti-fibrotic drugs could target lysophosphatidic acid, which has also been shown to block collagen type 1 production by chondrocytes and stromal cells in vitro 18 .…”

Section: Discussionmentioning

confidence: 99%

“…12 There is also accumulating evidence from human OA studies for scarring responses in bone, 13,14 meniscus and cartilage, 15 as well as joint capsule and synovium, 16 with similar findings in animal models of OA. [17][18][19] These suggested that fibrotic scarring of joint tissues represents a potentially important drug target for OA therapy. Anti-fibrotics that are commonly used for lung and kidney fibrosis have shown both safety and efficacy with extended use.…”

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confidence: 99%

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Pirfenidone reduces subchondral bone loss and fibrosis after murine knee cartilage injury

Chan

Luo

et al. 2017

Journal Orthopaedic Research

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Pirfenidone is an anti-inflammatory and anti-fibrotic drug that has shown efficacy in lung and kidney fibrosis. Because inflammation and fibrosis have been linked to the progression of osteoarthritis, we investigated the effects of oral Pirfenidone in a mouse model of cartilage injury, which results in chronic inflammation and joint-wide fibrosis in mice that lack hyaluronan synthase 1 (Has1 ) in comparison to wild-type. Femoral cartilage was surgically injured in wild-type and Has1 mice, and Pirfenidone was administered in food starting after 3 days. At 4 weeks, Pirfenidone reduced the appearance, on micro-computed tomography, of pitting in subchondral bone at, and cortical bone surrounding, the site of cartilage injury. This corresponded with a reduction in fibrotic tissue deposits as observed with gross joint surface photography. Pirfenidone resulted in significant recovery of trabecular bone parameters affected by joint injury in Has1 mice, although the effect in wild-type was less pronounced. Pirfenidone also increased Safranin-O staining of growth plate cartilage after cartilage injury and sham operation in both genotypes. Taken together with the expression of selected extracellular matrix, inflammation, and fibrosis genes, these results indicate that Pirfenidone may confer chondrogenic and bone-protective effects, although the well-known anti-fibrotic effects of Pirfenidone may occur earlier in the wound-healing response than the time point examined in this study. Further investigations to identify the specific cell populations in the joint and signaling pathways that are responsive to Pirfenidone are warranted, as Pirfenidone and other anti-fibrotic drugs may encourage tissue repair and prevent progression of post-traumatic osteoarthritis. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:365-376, 2018.

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Unfolding the Mystery Behind the Onset of Chondrocyte Hypertrophy during Chondrogenesis: Toward Designing Advanced Permanent Cartilage‐mimetic Biomaterials

Majumder

Ghosh

2023

Adv Funct Materials

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Successful recapitulation of the anatomical microarchitecture and biomechanics of the native articular cartilage under in vitro culture conditions is still an elusive topic of research. The major roadblock lies in maintaining the stable chondrogenic phenotype in vivo or under long‐term in vitro conditions. Tissue engineers worldwide has coined this aberrant loss of permanent cartilage characteristics to transient cartilage form as “chondrocyte hypertrophy”. Although the following has been validated through the expression of a few known markers but very little is understood regarding the molecular mechanism that dwells underneath. This review summarizes the precise aetiology behind the development and progression of the hypertrophic phenotype in chondrocytes under in vitro chondrogenic conditions. Based on the current literature survey, it is deciphered that the type of cell utilized (chondrocytes or stem cells), the chondrogenic culture conditions (growth factors/biochemical mediators) and the culture microenvironment (oxygen tension, mechanical loading) during chondrogenesis have a direct correlation with the dysregulated activity of the chondrogenic signaling pathways corroborating the onset of hypertrophic maturation of chondrocytes. Furthermore, it is critically analyzed whether to completely inhibit these hypertrophy‐inducing signaling pathways or apply a brake in terms of time‐dependent dose due to their functional duality role in chondrogenesis.

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Lysophosphatidic acid mediates fibrosis in injured joints by regulating collagen type I biosynthesis

Cited by 24 publications

References 44 publications

Thematic Review Series: Phospholipases: Central Role in Lipid Signaling and Disease Autotaxin, a lysophospholipase D with pleomorphic effects in oncogenesis and cancer progression

Thematic Review Series: Phospholipases: Central Role in Lipid Signaling and Disease Autotaxin, a lysophospholipase D with pleomorphic effects in oncogenesis and cancer progression

Pirfenidone reduces subchondral bone loss and fibrosis after murine knee cartilage injury

Unfolding the Mystery Behind the Onset of Chondrocyte Hypertrophy during Chondrogenesis: Toward Designing Advanced Permanent Cartilage‐mimetic Biomaterials

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