Matrix Disruptions, Growth, and Degradation of Cartilage with Impaired Sulfation

Mertz, Edward L.; Facchini, Marcella; Pham, Anna; Gualeni, Benedetta; Leonardis, Fabio De; Rossi, Antonio; Forlino, Antonella

doi:10.1074/jbc.m110.116467

Cited by 24 publications

(31 citation statements)

References 67 publications

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“…The resulting matrix layer was fixed in 0.7% formaldehyde at room temperature for 4-6 h. 5 μm cryosections of the matrix were cut perpendicular to the matrix layer as described above, briefly washed (with PBS and 2 mM CaCl 2 , 150 mM NaCl, pH~7.5), sealed between two 2 mm BaF 2 windows in a flow-through high definition infra-red (HDIR) chamber [36] thermostated at 20.0°C, and hydrated in a CaCl 2 -NaCl-NaF (CNF) solution (2 mM CaCl 2 , 150 mM NaCl, 10 μm NaF, pH~7.5).…”

Section: Methodsmentioning

confidence: 99%

“…Visible transmission images were recorded via a reflective 15x/0.4NA objective in a Hyperion 3000/Vertex 70 infrared microscope/spectrometer (Bruker Optics). Sections were de-stained by flushing CNF solution, and hyper-spectral infrared images were recorded for 30 min with 4cm -1 spectral and 2.8 μm pixel resolutions via the infrared microscope equipped with a 128×128 array detector as described in [36]. The infrared absorption spectra at each pixel were corrected for water contribution.…”

Section: Methodsmentioning

confidence: 99%

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Makings of a brittle bone: Unexpected lessons from a low protein diet study of a mouse OI model

et al. 2016

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Glycine substitutions in type I collagen appear to cause osteogenesis imperfecta (OI) by disrupting folding of the triple helix, the structure of which requires Gly in every third position. It is less clear, however, whether the resulting bone malformations and fragility are caused by effects of intracellular accumulation of misfolded collagen on differentiation and function of osteoblasts, effects of secreted misfolded collagen on the function of bone matrix, or both. Here we describe a study originally conceived for testing how reducing intracellular accumulation of misfolded collagen would affect mice with a Gly610 to Cys substitution in the triple helical region of the α2(I) chain. To stimulate degradation of misfolded collagen by autophagy, we utilized a low protein diet. The diet had beneficial effects on osteoblast differentiation and bone matrix mineralization, but it also affected bone modeling and suppressed overall animal growth. Our more important observations, however, were not related to the diet. They revealed how altered osteoblast function and deficient bone formation by each cell caused by the G610C mutation combined with increased osteoblastogenesis might make the bone more brittle, all of which are common OI features. In G610C mice, increased bone formation surface compensated for reduced mineral apposition rate, resulting in normal cortical area and thickness at the cost of altering cortical modeling process, retaining woven bone, and reducing the ability of bone to absorb energy through plastic deformation. Reduced collagen and increased mineral density in extracellular matrix of lamellar bone compounded the problem, further reducing bone toughness. The latter observations might have particularly important implications for understanding OI pathophysiology and designing more effective therapeutic interventions.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Makings of a brittle bone: Unexpected lessons from a low protein diet study of a mouse OI model

et al. 2016

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“…However, DTD is characterized by other aberrant functions of chondrocytes, including reduction in cartilage, irregular chondrocyte size, reduced chondrocyte proliferation, and lack of terminal chondrocyte differentiation. These are unlikely to result solely from defective proteoglycan sulfation (11,13,14).…”

Section: Discussionmentioning

confidence: 99%

“…However, the multiple skeletal abnormalities in DTD, including reduced cartilage volume, irregular chondrocyte size, reduced chondrocyte proliferation, and lack of terminal chondrocyte differentiation (11,13,14), suggest that Slc26a2 may have additional roles in chondrocyte biology.…”

Section: Slc26a2 Expression Level Correlates With Mesenchymal Cellmentioning

confidence: 99%

“…The skeletal phenotype is typified by reduction of cartilage, irregular chondrocyte size, delayed secondary ossification center formation, and osteoporosis of the long bones. Moreover, reduced chondrocyte proliferation and lack of terminal differentiation likely contribute to reduced bone growth in DTD (11,13,14). Thus, the growth plate height and the number of cartilage-forming chondrocytes are greatly reduced in the Slc26a2 mutant mouse (15).…”

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confidence: 99%

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Multiple Roles of the SO42−/Cl−/OH− Exchanger Protein Slc26a2 in Chondrocyte Functions

Park

Ohana

Choi

et al. 2014

Journal of Biological Chemistry

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Background: Slc26a2 is a SO 4 2Ϫ transporter that is mutated in diastrophic dysplasia. The role of Slc26a2 in several chondrocyte functions is unknown. Results: Slc26a2 is activated by IGF-1 to regulate chondrocyte, proliferation, differentiation, proteoglycan synthesis, and size. Conclusion: Slc26a2 regulates multiple SO 4 2Ϫ -dependent and SO 4 2Ϫ -independent chondrocyte functions. Significance: The findings should help in understanding aberrant SLC26A2 function in diastrophic dysplasia.

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Sulfated Hydrogel Matrices Direct Mitogenicity and Maintenance of Chondrocyte Phenotype through Activation of FGF Signaling

Öztürk

Arlov

Aksel

et al. 2016

Adv Funct Materials

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Deciphering the roles of chemical and physical features of the extracellular matrix (ECM) is vital for developing biomimetic materials with desired cellular responses in regenerative medicine. Here, we demonstrate that sulfation of biopolymers, mimicking the proteoglycans in native tissues, induces mitogenicity, chondrogenic phenotype, and suppresses catabolic activity of chondrocytes, a cell type that resides in a highly sulfated tissue. We show through tunable modification of alginate that increased sulfation of the microenvironment promotes FGF signaling-mediated proliferation of chondrocytes in a three-dimensional (3D) matrix independent of stiffness, swelling, and porosity. Furthermore, we show for the first time that a biomimetic hydrogel acts as a 3D signaling matrix to mediate a heparan sulfate/heparin-like interaction between FGF and its receptor leading to signaling cascades inducing cell proliferation, cartilage matrix production, and suppression of de-differentiation markers. Collectively, this study reveals important insights on mimicking the ECM to guide self-renewal of cells via manipulation of distinct signaling mechanisms.

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Matrix Disruptions, Growth, and Degradation of Cartilage with Impaired Sulfation

Cited by 24 publications

References 67 publications

Makings of a brittle bone: Unexpected lessons from a low protein diet study of a mouse OI model

Makings of a brittle bone: Unexpected lessons from a low protein diet study of a mouse OI model

Multiple Roles of the SO42−/Cl−/OH− Exchanger Protein Slc26a2 in Chondrocyte Functions

Sulfated Hydrogel Matrices Direct Mitogenicity and Maintenance of Chondrocyte Phenotype through Activation of FGF Signaling

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