Agrin polypeptide and uses thereof

1 . A soluble polypeptide comprising the amino acid sequence of SEQ ID NO: 3 or a variant thereof having at least 98% sequence identity to SEQ ID NO: 3,

wherein the soluble polypeptide is a fragment of human agrin or a variant of human agrin and consists of up to 900 consecutive amino acids of said human agrin or said variant of human agrin; and

wherein the soluble polypeptide has the ability to induce chondrocyte differentiation and/or chondrogenesis.

2 . The soluble polypeptide of claim 1 , consisting of up to 850 or 802 consecutive amino acids of said human agrin or said variant of human agrin.

3 . The soluble polypeptide of claim 1 , comprising or consisting of the amino acid sequence of SEQ ID NO: 3.

4 . The soluble polypeptide of claim 1 , wherein the soluble polypeptide is resistant to cleavage by MMP3.

5 . The soluble polypeptide of claim 4 , wherein at least one amino acid selected from the amino acids corresponding to positions 1753, 1754, 1755, 1756, 1757 and 1758 of SEQ ID NO: 1 is deleted or substituted with another amino acid.

6 . The soluble polypeptide of claim 1 , wherein the soluble polypeptide is a recombinant polypeptide.

7 . The soluble polypeptide of claim 1 , wherein the soluble polypeptide retains:

a) an ability to promote differentiation of chondrocytes;

b) an ability to induce chondrogenesis in mesenchymal stem cells;

c) an inability to induce MMP-13 or COL10A1 expression;

d) an ability to induce SOX9 expression;

e) an ability to induce COL2A1 expression;

f) an ability to induce aggrecan expression;

g) an ability to induce cartilage production; and/or

h) an ability to induce the differentiation of mesenchymal stem cells of synovial membrane origin or mesenchymal stem cells of GDF5 lineage, as compared to the human agrin of SEQ ID NO: 1.

8 . A polynucleotide encoding the soluble polypeptide of claim 1 .

9 . A composition comprising the soluble polypeptide of claim 1 and at least one pharmaceutically acceptable diluent, carrier, or preservative.

10 . A method of treating osteoarthritis or an osteochondral defect in a subject, the method comprising administering to the subject the composition of claim 9 .

11 . The method of claim 10 , wherein administering the composition comprises intra-articular or systemic delivery.

12 . A method for inducing chondrogenic differentiation of mesenchymal stem cells, comprising contacting the mesenchymal stem cells with the soluble polypeptide of claim 1 .

13 . The method of claim 12 , wherein the mesenchymal stem cells are of GDF5 lineage.

14 . The method of claim 12 , wherein the mesenchymal stem cells are of synovial membrane origin.