Hyperglycemia Diverts Dividing Osteoblastic Precursor Cells to an Adipogenic Pathway and Induces Synthesis of a Hyaluronan Matrix That Is Adhesive for Monocytes

Wang, Aimin; Midura, Ronald J.; Vasanji, Amit; Wang, Andrew J.; Hascall, Vincent C.

doi:10.1074/jbc.m113.541458

Cited by 57 publications

(39 citation statements)

References 66 publications

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“…Monocytes recognize and adhere to these modified HA structures (14, 21). These leukocyte-adhesive HA matrices are present in many pathological conditions, including lung biopsies from asthmatic patients (21), responses of smooth muscle cells to ER stress at physiological normal levels of glucose (31,32), wound healing (33), idiopathic pulmonary hypertension (18), airway smooth muscle cells in vitro (32), airway interstitial cells in mouse asthma models (19), renal tubular endothelial stress (34,35), and adipocytes in a diabetic rat model (36,37). However, in this study we show that murine AECs behave differently than the other cell types reported so far.…”

Section: Discussionmentioning

confidence: 99%

Hyaluronan Rafts on Airway Epithelial Cells

Abbadi

Lauer²,

Swaidani

et al. 2016

Journal of Biological Chemistry

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Many cells, including murine airway epithelial cells, respond to a variety of inflammatory stimuli by synthesizing leukocyteadhesive hyaluronan (HA) cables that remain attached to their cell surfaces. This study shows that air-liquid interface cultures of murine airway epithelial cells (AECs) also actively synthesize and release a majority of their HA onto their ciliated apical surfaces to form a heavy chain hyaluronan (HC-HA) matrix in the absence of inflammatory stimuli. These matrices do not resemble the rope-like HA cables but occur in distinct sheets or rafts that can capture and embed leukocytes from cell suspensions. The HC-HA modification involves the transfer of heavy chains from the inter-␣-inhibitor (I␣I) proteoglycan, which has two heavy chains (HC1 and HC2) on its chondroitin sulfate chain. The transesterification transfer of HCs from chondroitin sulfate to HA is mediated by tumor necrosis factor-induced gene 6 (TSG-6), which is up-regulated in inflammatory reactions. Because the AEC cultures do not have TSG-6 nor serum, the source of I␣I, assays for HCs and TSG-6 were done. The results show that AECs synthesize TSG-6 and their own heavy chain donor (pre-I␣I) with a single heavy chain 3 (HC3), which are also constitutively expressed by human renal proximal tubular epithelial cells. These leukocyte adhesive HC3-HA structures were also found in the bronchoalveolar lavage of naïve mice and were observed on their apical ciliated surfaces. Thus, these leukocyteadhesive HA rafts are now identified as HC3-HA complexes that could be part of a host defense mechanism filling some important gaps in our current understanding of murine airway epithelial biology and secretions.

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Section: Discussionmentioning

confidence: 99%

Hyaluronan Rafts on Airway Epithelial Cells

Abbadi

Lauer²,

Swaidani

et al. 2016

Journal of Biological Chemistry

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“…Additionally, several soluble growth factors and cytokines[21-25] in the extracellular matrix (ECM)[26, 27] have a role in directing the fate of these cells. Native hyaluronan (HA) and osteopontin, which are ligands for CD44, support the proliferation and differentiation of these adipose derived stem cells into adipocytes[28-32]. While native, high molecular weight HA supports survival, proliferation and differentiation of pre-adipocytes, fragmentation of HA suppresses adipocyte maturation.…”

Section: Introductionmentioning

confidence: 99%

Receptor for hyaluronan mediated motility (RHAMM/HMMR) is a novel target for promoting subcutaneous adipogenesis

et al. 2017

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Hyaluronan, CD44 and the Receptor for Hyaluronan-Mediated Motility (RHAMM, gene name HMMR) regulate stem cell differentiation including mesenchymal progenitor differentiation. Here, we show that CD44 expression is required for subcutaneous adipogenesis, whereas RHAMM expression suppresses this process. We designed RHAMM function blocking peptides to promote subcutaneous adipogenesis as a clinical and tissue engineering tool. Adipogenic RHAMM peptides were identified by screening for their ability to promote adipogenesis in culture assays using rat bone marrow mesenchymal stem cells, mouse pre-adipocyte cell lines and primary human subcutaneous pre-adipocytes. Oil red O uptake into fat droplets and adiponectin production were used as biomarkers of adipogenesis. Positive peptides were formulated in either collagen I or hyaluronan (Orthovisc) gels then assessed for their adipogenic potential in vivo following injection into dorsal rat skin and mammary fat pads. Fat content was quantified and characterized using micro CT imaging, morphometry, histology, RT-PCR and ELISA analyses of adipogenic gene expression. Injection of screened peptides increased dorsal back subcutaneous fat pad area (208.3 ± 10.4 mm2 versus control 84.11 ± 4.2 mm2; p < 0.05) and mammary fat pad size (45 ± 11 mg above control background, p=0.002) in female rats. This effect lasted >5 weeks as detected by micro CT imaging and perilipin 1 mRNA expression. RHAMM expression suppresses while blocking peptides promote expression of PPARγ, C/EBP and their target genes. Blocking RHAMM function by peptide injection or topical application is a novel and minimally invasive method for potentially promoting subcutaneous adipogenesis in lipodystrophic diseases and a complementary tool to subcutaneous fat augmentation techniques.

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“…16,17 In the insulin-deficient form of the disease, this leads to diminished bone density, with human studies and streptozotocin-induced diabetic animal models noting a decrease in trabecular bone mass and a reciprocal increase in the adiposity of the marrow. [16][17][18][19][20] Alternatively, analyses of bones of type 2 diabetics have generally observed unchanged or increased bone mineral density, though clinically, both diabetic populations have a substantially increased risk of fractures in comparison to non-diabetics. 18,[21][22][23][24] Additionally, there is increasing evidence that some diabetic medications may negatively impact bone density and marrow adiposity.…”

Section: Diabetes and Its Complicationsmentioning

confidence: 99%