Chondrogenic induction by bone morphogenetic protein-2: Involvement of N-cadherin-associated functions

1997 1997

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Abstract (summary)

Transforming growth factor-$\beta$ superfamily members induce chondrogenic differentiation, and several studies have reported that these factors can regulate the expression of cell adhesion molecules. The Ca$\sp{2+}$-dependent cell adhesion molecule, N-cadherin, plays a functional role in chondrogenesis. This thesis research investigates the regulation of N-cadherin-dependent cell adhesion by bone morphogenetic protein-2 (BMP-2) during chondrogenesis and the signaling events downstream of BMP-2 and/or N-cadherin required for chondrogenesis. The murine multipotential cell line, C3H10T1/2, is used as the model system as these cells undergo chondrogenesis when treated with TGF-$\beta$1 or BMP-2. The thesis research presented here demonstrated that within 24 hours of BMP-2 treatment, C3H10T1/2 cells in high density micromass culture exhibit a 4-fold upregulation of N-cadherin mRNA, and by day 5 an 8-fold upregulation of N-cadherin protein. BMP-2 upregulation of N-cadherin expression and resultant chondrogenesis required mitogsn activated protein kinase (MAPK) activity and tyrosine phosphorylation as downstream events. Several studies demonstrated that BMP-2 upregulation of N-cadherin expression was functionally required for chondrogenesis: (1) peptides which block N-cadherin function inhibited BMP-2 induced chondrogenesis; (2) recombinant overexpression of full length N-cadherin enhanced chondrogenesis when overexpressed at a moderate level, and decreased chondrogenesis when overexpressed at a high level; and (3) recombinant expression of a dominant negative N-cadherin mutant molecule inhibited chondrogenesis. Other laboratories have recently reported that N-cadherin dependent cell adhesion requires intracellular associations with $\alpha $-, $\beta$-, and $\gamma$-catenin, and that the protein adenomatous polyposis coli (APC) may play a role in regulating these interactions. The research presented here demonstrated that BMP-2 not only modulated N-cadherin function by decreasing the overall association of catenins with N-cadherin, but also regulated the intracellular levels and distribution of $\beta$-catenin-levels were maintained in BMP-2 treated cultures, but were redistributed to a cytoplasmic, non-N-cadherin-associated pool. Furthermore, the association of $\beta$-catenin with APC was significantly diminished in BMP-2 cultures when the cytoplasmic pool began to appear. The results presented here indicate that BMP-2 requires the upregulation of N-cadherin expression and function to induce chondrogenesis, and alterations in N-cadherin dependent cell-cell adhesion at the cadherin-catenin complex level occur as cells begin to differentiate.

Indexing (details)

Cellular biology;
Molecular biology;
0379: Cellular biology
0307: Molecular biology
0487: Biochemistry
Identifier / keyword
Pure sciences; Biological sciences; Bone; Cadherin; Chondrogenic; Morphogenetic protein-2
Chondrogenic induction by bone morphogenetic protein-2: Involvement of N-cadherin-associated functions
Haas, Andrew Robert
Number of pages
Publication year
Degree date
School code
DAI-B 59/07, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
9780591939897, 0591939894
Tuan, Rocky S.
Thomas Jefferson University
University location
United States -- Pennsylvania
Source type
Dissertations & Theses
Document type
Dissertation/thesis number
ProQuest document ID
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
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