Glycosaminoglycan synthesis by the apical ectodermal ridge of chick limb bud

Kosher, Robert A.; Savage, Mary P.

doi:10.1038/291231a0

Cited by 34 publications

(6 citation statements)

References 15 publications

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“…While it remains possible that UGDH has some hitherto undefined and indirect effect on in vitro chondrogenesis, the enhanced cartilage formation associated with contrasting effects on sGAG and HA release in this context (decreased HA and increased sGAG release after 6 days) suggests a UGDH‐mediated acceleration of chondrogenesis also involves the suppression of HA release. This agrees with recent studies in which HAS‐2 overexpression was sufficient to restrict chondrogenesis (Li et al, 2007) and is consistent with the proposal that selective decreases in HA production are necessary for the close cellular juxtaposition in pre‐cartilaginous condensations required to trigger chondrogenic differentiation (Kosher and Savage, 1981). These possibilities suggest that specific consideration should be given, in future studies, to whether UGDH is acting exclusively on local, pericellular matrix production or whether it may lead to alterations in HA and sGAG assembly in more distant ECM locations further from the chondron.…”

Section: Discussionsupporting

confidence: 93%

Regulation of UDP‐glucose dehydrogenase is sufficient to modulate hyaluronan production and release, control sulfated GAG synthesis, and promote chondrogenesis

Clarkin

Allen

Kuiper

et al. 2010

Journal Cellular Physiology

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Glycosaminoglycans (GAGs) are critical for extracellular matrix (ECM) integrity in cartilage but mechanisms regulating their synthesis are not defined. UDP-glucose dehydrogenase (UGDH) catalyses UDP-glucose oxidation to UDP-glucuronic acid, an essential monosaccharide in many GAGs. Our previous studies in articular surface (AS) cells from embryonic joints have established pivotal roles for mitogen-activated protein kinases (MAPK) in synthesis of the unsulfated GAG, hyaluronan (HA). We investigated the functional significance of UGDH in GAG production and chondrogenesis, and determined roles for MEK-ERK and p38MAPK pathways in regulating UGDH expression and function. Inhibitors of MEK and p38MAPK reduced UGDH protein in AS cells. Treatment with TGF-β (archetypal growth factor) increased UGDH expression, sulfated (s)-GAG/HA release and pericellular matrix formation in a p38MAPK-dependent manner. Retroviral overexpression of UGDH augmented HA/sGAG release and pericellular matrix elaboration, which were blocked by inhibiting MEK but not p38MAPK. UGDH overexpression increased cartilage nodule size in bone marrow culture, promoted chondrogenesis in limb bud micromass culture and selectively suppressed medium HA levels and modified GAG sulfation, as assessed by FACE analysis. Our data provide evidence that: (i) TGF-β regulates UGDH expression via p38MAPK to modulate sGAG/HA secretion, (ii) MEK-ERK, but not p38MAPK facilitates UGDH-induced HA and sGAG release, and (iii) increased UGDH expression promotes chondrogenesis directly and differential modifies GAG levels and sulfation. These results indicate a more diverse role for UGDH in the support of selective GAG production than previously described. Factors regulating UGDH may provide novel candidates for restoring ECM integrity in degenerative cartilage diseases, such as osteoarthritis.Arthritis Research Campaign.

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Section: Discussionsupporting

confidence: 93%

Regulation of UDP‐glucose dehydrogenase is sufficient to modulate hyaluronan production and release, control sulfated GAG synthesis, and promote chondrogenesis

Clarkin

Allen

Kuiper

et al. 2010

Journal Cellular Physiology

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“…Dramatically increased HA-rich matrix formation has been observed around proliferating and migrating cells during morphogenesis, regeneration and healing. High amounts of HA molecules are synthesized 1) prior to mesenchymal cell differentiation and throughout embryonic development, where the condensation and differentiation of the mesenchymal cells are accompanied by the spatial distribution of HA in the different regions of the limb bud [17][18][19], 2) During brain development around proliferating and migrating neuronal cells [20], and 3) during formation of heart valves when cushion cells migrate from the endocardium to the myocardium [10].…”

Section: Introductionmentioning

confidence: 99%

Hyaluronan and Hyaluronan Synthases: Potential Therapeutic Targets in Cancer

Adamia¹,

Maxwell²,

Pilarski

2005

CDTCHD

149

130

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Current models of oncogenesis describe cancer as a progression of genetic mutations in a tumor cell mass. However, tumors are more than a clonal expansion of malignant cells. Tumors are heterogeneous, with a complex 3D structure, analogous to organs comprised of different tissues. In a tumor mass, the component cell types interact with each other and with their microenvironment by exchanging information through cell-cell interactions and/or through interactions with the extracellular matrix (ECM). These synergetic interactions facilitate tumor progression. Furthermore, tumor invasion and metastatic development are accomplished through the breakdown of ECM. Disruption of ECM promotes abnormal inter- and/or intra- cellular signaling, leading to dysregulation of cell proliferation, growth and cytoskeleton reorganization. The disruption of the ECM in turn promotes the overproduction of growth factors, which induce elevated epithelial cell proliferation and other abnormalities including carcinogenesis. In this review we will demonstrate that hyaluronan (HA), a core component of ECM, contributes to certain types of cancer development. Additional to extracellular HA, intracellular and nuclear forms of HA have been detected. Intracellular HA is involved in cell signaling, whereas nuclear HA could promote chromatin condensation and thus facilitate mitosis. HA molecules are synthesized by hyaluronan synthases (HASs)-HAS1, HAS2 and HAS3 enzymes. Dysregulation of HAS genes results in abnormal production of HA and promotion of abnormal biological processes such as transformation and metastasis. The function of HASs appears to be cell and tissue specific. HAS1 maintains a low, basal level of HA. HAS2 is involved in embryonic and cardiac cushion morphogenesis and subsequent development through cell migration and invasion. HAS2 stimulates cell proliferation and angiogenesis. HAS3 appears to favor the malignant phenotype in many types of malignancies. However, the exact function of HAS isoenzymes and their role in cell signaling remains to be elucidated. A better understanding of HA and HASs may facilitate the design of novel therapeutic strategies to counter presumptive cancer-promoting effects of microenvironmental components.

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“…Several morphogenetic and biochemical characteristics of the early avian limb bud influence the course of its differentiation and development. They include : the apical ectoder-ma1 ridge (AER) [18,331; the proximal epithelium [18,[32][33][34]361; the zone of polarizing activity (ZPA) [14]; regional vascularization [5,151; the collagen matrix [38, 391; glycosaminoglycans 19, 25, 311; cyclic AMP [18, 351; alltrans retinoic acid [37]; nicotinamide and/or NAD [4,24,26, 291 and molecular oxygen [5]. Of particular interest to us were the possible determinative roles of molecular oxygen and NAD.…”

Section: Introductionmentioning

confidence: 99%