Kindlin-3 Mutation in Mesenchymal Stem Cells Results in Enhanced Chondrogenesis

Overview

Journal Exp Cell Res

Specialty Cell Biology

Date 2021 Jan 8

PMID 33417921

Citations 8

Authors

Bethany A Kerr

Lihong Shi

Alexander H Jinnah

Koran S Harris

Jeffrey S Willey

Donald P Lennon

Arnold I Caplan

Tatiana V Byzova

Affiliations

Soon will be listed here.

Abstract

Identifying patient mutations driving skeletal development disorders has driven our understanding of bone development. Integrin adhesion deficiency disease is caused by a Kindlin-3 (fermitin family member 3) mutation, and its inactivation results in bleeding disorders and osteopenia. In this study, we uncover a role for Kindlin-3 in the differentiation of bone marrow mesenchymal stem cells (BMSCs) down the chondrogenic lineage. Kindlin-3 expression increased with chondrogenic differentiation, similar to RUNX2. BMSCs isolated from a Kindlin-3 deficient patient expressed chondrocyte markers, including SOX9, under basal conditions, which were further enhanced with chondrogenic differentiation. Rescue of integrin activation by a constitutively activated β integrin construct increased adhesion to multiple extracellular matrices and reduced SOX9 expression to basal levels. Growth plates from mice expressing a mutated Kindlin-3 with the integrin binding site ablated demonstrated alterations in chondrocyte maturation similar to that seen with the human Kindlin-3 deficient BMSCs. These findings suggest that Kindlin-3 expression mirrors RUNX2 during chondrogenesis.

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References

Meller J, Chen Z, Dudiki T, Cull R, Murtazina R, Bal S . Integrin-Kindlin3 requirements for microglial motility in vivo are distinct from those for macrophages. JCI Insight. 2017; 2(11). PMC: 5453700. DOI: 10.1172/jci.insight.93002. View

Olivares-Navarrete R, Lee E, Smith K, Hyzy S, Doroudi M, Williams J . Substrate Stiffness Controls Osteoblastic and Chondrocytic Differentiation of Mesenchymal Stem Cells without Exogenous Stimuli. PLoS One. 2017; 12(1):e0170312. PMC: 5240960. DOI: 10.1371/journal.pone.0170312. View

Koshimizu T, Kawai M, Kondou H, Tachikawa K, Sakai N, Ozono K . Vinculin functions as regulator of chondrogenesis. J Biol Chem. 2012; 287(19):15760-75. PMC: 3346098. DOI: 10.1074/jbc.M111.308072. View

Crazzolara R, Maurer K, Schulze H, Zieger B, Zustin J, Schulz A . A new mutation in the KINDLIN-3 gene ablates integrin-dependent leukocyte, platelet, and osteoclast function in a patient with leukocyte adhesion deficiency-III. Pediatr Blood Cancer. 2015; 62(9):1677-9. DOI: 10.1002/pbc.25537. View

Malinin N, Zhang L, Choi J, Ciocea A, Razorenova O, Ma Y . A point mutation in KINDLIN3 ablates activation of three integrin subfamilies in humans. Nat Med. 2009; 15(3):313-8. PMC: 2857384. DOI: 10.1038/nm.1917. View

Ikegami D, Akiyama H, Suzuki A, Nakamura T, Nakano T, Yoshikawa H . Sox9 sustains chondrocyte survival and hypertrophy in part through Pik3ca-Akt pathways. Development. 2011; 138(8):1507-19. DOI: 10.1242/dev.057802. View

McCabe N, Kerr B, Madajka M, Vasanji A, Byzova T . Augmented osteolysis in SPARC-deficient mice with bone-residing prostate cancer. Neoplasia. 2011; 13(1):31-9. PMC: 3022426. DOI: 10.1593/neo.10998. View

Terpstra L, Prudhomme J, Arabian A, Takeda S, Karsenty G, Dedhar S . Reduced chondrocyte proliferation and chondrodysplasia in mice lacking the integrin-linked kinase in chondrocytes. J Cell Biol. 2003; 162(1):139-48. PMC: 2172728. DOI: 10.1083/jcb.200302066. View

Hausler G, Helmreich M, Marlovits S, Egerbacher M . Integrins and extracellular matrix proteins in the human childhood and adolescent growth plate. Calcif Tissue Int. 2002; 71(3):212-8. DOI: 10.1007/s00223-001-2083-x. View

10.

Matus D, Chang E, Makohon-Moore S, Hagedorn M, Chi Q, Sherwood D . Cell division and targeted cell cycle arrest opens and stabilizes basement membrane gaps. Nat Commun. 2014; 5:4184. PMC: 4138880. DOI: 10.1038/ncomms5184. View

11.

Bialkowska K, Ma Y, Bledzka K, Sossey-Alaoui K, Izem L, Zhang X . The integrin co-activator Kindlin-3 is expressed and functional in a non-hematopoietic cell, the endothelial cell. J Biol Chem. 2010; 285(24):18640-9. PMC: 2881789. DOI: 10.1074/jbc.M109.085746. View

12.

Xu Z, Chen X, Zhi H, Gao J, Bialkowska K, Byzova T . Direct interaction of kindlin-3 with integrin αIIbβ3 in platelets is required for supporting arterial thrombosis in mice. Arterioscler Thromb Vasc Biol. 2014; 34(9):1961-7. PMC: 4167429. DOI: 10.1161/ATVBAHA.114.303851. View

13.

Dy P, Wang W, Bhattaram P, Wang Q, Wang L, Ballock R . Sox9 directs hypertrophic maturation and blocks osteoblast differentiation of growth plate chondrocytes. Dev Cell. 2012; 22(3):597-609. PMC: 3306603. DOI: 10.1016/j.devcel.2011.12.024. View

14.

Solursh M, Linsenmayer T, Jensen K . Chondrogenesis from single limb mesenchyme cells. Dev Biol. 1982; 94(1):259-64. DOI: 10.1016/0012-1606(82)90090-2. View

15.

Uckan D, Kilic E, Sharafi P, Kazik M, Kaya F, Erdemli E . Adipocyte differentiation defect in mesenchymal stromal cells of patients with malignant infantile osteopetrosis. Cytotherapy. 2009; 11(4):392-402. DOI: 10.1080/14653240802582083. View

16.

Grashoff C, Aszodi A, Sakai T, Hunziker E, Fassler R . Integrin-linked kinase regulates chondrocyte shape and proliferation. EMBO Rep. 2003; 4(4):432-8. PMC: 1319157. DOI: 10.1038/sj.embor.embor801. View

17.

Dennis J, Konstantakos E, Arm D, Caplan A . In vivo osteogenesis assay: a rapid method for quantitative analysis. Biomaterials. 1998; 19(15):1323-8. DOI: 10.1016/s0142-9612(97)00170-1. View

18.

Ussar S, Wang H, Linder S, Fassler R, Moser M . The Kindlins: subcellular localization and expression during murine development. Exp Cell Res. 2006; 312(16):3142-51. DOI: 10.1016/j.yexcr.2006.06.030. View

19.

Plow E, Qin J, Byzova T . Kindling the flame of integrin activation and function with kindlins. Curr Opin Hematol. 2009; 16(5):323-8. PMC: 3628604. DOI: 10.1097/MOH.0b013e32832ea389. View

20.

McCabe N, De S, Vasanji A, Brainard J, Byzova T . Prostate cancer specific integrin alphavbeta3 modulates bone metastatic growth and tissue remodeling. Oncogene. 2007; 26(42):6238-43. PMC: 2753215. DOI: 10.1038/sj.onc.1210429. View