Development - Osteopontin signaling in osteoclasts

Osteopontin signaling in osteoclasts

Osteopontin is an RGD-containing bone matrix protein which plays a key role in osteoclast activation and function.

Osteopontin binds through its alpha-V/beta-3 integrin receptor on the osteoclast plasma membrame and provides osteoclasts attachment to bone surface [1]. Also it can bind to CD44 surface receptor. CD44 is implicated in chemotaxis mediated by Osteopontin [1], [2].

In addition, Osteopontin plays a role in regulating bone matrix stability by preventing Hydroxyapatite crystal growth and inhibiting tooth mineralization [3], [4].

In osteoclasts, osteopontin acts through alpha-V/beta-3 integrin. Activated alpha-V/beta-3 integrin binds to V-src sarcoma viral oncogene homolog (c-Src), which, subsequently, activates Syk and VAV-3 which leads to RhoA activation [5], [6]. RhoA binds to PIP5KI and stimulates production of PtdIns(4,5)P2 . PtdIns(4,5)P2 binds to DBS and, thus, promotes CDC42 activation [7]. CDC42 and PtdIns(4,5)P2 binds to WASP and promotes its association with Arp2/3 and Actin cytoskeletal. It leads to the formation of actin ring and activation of bone resorption [8], [9].

Osteopontin-stimulated RhoA also activates phosphoinositide-3-kinase, probably via binding to FAK1 and FAK1 activation of Phosphoinositide-3-kinase, PI3K reg class IA (p85-alpha) [10], [11]. In addition, Osteopontin-activated c-Src promotes PI3K reg class IA (p85-alpha) activation [12], [13]. It recruits PI3K cat class IA (p110-alpha) and stimulates synthesis of PtdIns(3,4,5)P3 and PtdIns(4,5)P2 . PtdIns(3,4)P2 , PtdIns(3,4,5)P3 and PtdIns(4,5)P2 (produced by the activated PIP5KI) associate with Gelsolin. This event promotes formation of the podosome, followed by uncapping the actin barbed ends, actin filament elongation and, finally, osteoclast adhesion and migration to the bone surface [9], [10], [14], [15].

Osteopontin-activated c-Src induces phosphorylation of Pyk2(FAK2), which associates with p130CAS. p130CAS binds to Gelsolin and promotes podosome formation and osteoclast activation [16], [17].

In addition, Osteopontin induces RhoA-dependent ROCK2 activation, which leads to ROCK2-mediated phosphorylation of CD44 and MSN (moesin) and surface expression of CD44. It also promotes CD44 association with VIL2 (ezrin) and MSN (moesin) and leads to actin cytoskeleton reorganization, thus increasing osteoclast motility and bone resorption [2], [18].

Objects list:

References:

1. Chellaiah MA, Hruska KA
   The integrin alpha(v)beta(3) and CD44 regulate the actions of osteopontin on osteoclast motility. Calcified tissue international 2003 Mar;72(3):197-205
2. Chellaiah MA, Biswas RS, Rittling SR, Denhardt DT, Hruska KA
   Rho-dependent Rho kinase activation increases CD44 surface expression and bone resorption in osteoclasts. The Journal of biological chemistry 2003 Aug 1;278(31):29086-97
3. Herijgers P, Overloop K, Toshima Y, Van Hecke P, Vanstapel F, Mubagwa K, Flameng W
   Ischaemic ATP degradation studied by HPLC and 31P-NMR spectroscopy: do the two techniques observe the same ATP pools? Basic research in cardiology 1994 Jan-Feb;89(1):50-60
4. Standal T, Borset M, Sundan A
   Role of osteopontin in adhesion, migration, cell survival and bone remodeling. Experimental oncology 2004 Sep;26(3):179-84
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   Vav3 regulates osteoclast function and bone mass. Nature medicine 2005 Mar;11(3):284-90
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   Syk, c-Src, the alphavbeta3 integrin, and ITAM immunoreceptors, in concert, regulate osteoclastic bone resorption. The Journal of cell biology 2007 Mar 12;176(6):877-88
7. Rossman KL, Cheng L, Mahon GM, Rojas RJ, Snyder JT, Whitehead IP, Sondek J
   Multifunctional roles for the PH domain of Dbs in regulating Rho GTPase activation. The Journal of biological chemistry 2003 May 16;278(20):18393-400
8. Chellaiah MA
   Regulation of actin ring formation by rho GTPases in osteoclasts. The Journal of biological chemistry 2005 Sep 23;280(38):32930-43
9. Chellaiah MA
   Regulation of podosomes by integrin alphavbeta3 and Rho GTPase-facilitated phosphoinositide signaling. European journal of cell biology 2006 Apr;85(3-4):311-7
10. Chellaiah MA, Soga N, Swanson S, McAllister S, Alvarez U, Wang D, Dowdy SF, Hruska KA
    Rho-A is critical for osteoclast podosome organization, motility, and bone resorption. The Journal of biological chemistry 2000 Apr 21;275(16):11993-2002
11. Chellaiah MA, Biswas RS, Yuen D, Alvarez UM, Hruska KA
    Phosphatidylinositol 3,4,5-trisphosphate directs association of Src homology 2-containing signaling proteins with gelsolin. The Journal of biological chemistry 2001 Dec 14;276(50):47434-44
12. Hruska KA, Rolnick F, Huskey M, Alvarez U, Cheresh D
    Engagement of the osteoclast integrin alpha v beta 3 by osteopontin stimulates phosphatidylinositol 3-hydroxyl kinase activity. Endocrinology 1995 Jul;136(7):2984-92
13. Chellaiah M, Fitzgerald C, Alvarez U, Hruska K
    c-Src is required for stimulation of gelsolin-associated phosphatidylinositol 3-kinase. The Journal of biological chemistry 1998 May 8;273(19):11908-16
14. Chellaiah M, Hruska K
    Osteopontin stimulates gelsolin-associated phosphoinositide levels and phosphatidylinositol triphosphate-hydroxyl kinase. Molecular biology of the cell 1996 May;7(5):743-53
15. Biswas RS, Baker D, Hruska KA, Chellaiah MA
    Polyphosphoinositides-dependent regulation of the osteoclast actin cytoskeleton and bone resorption. BMC cell biology 2004 May 13;5:19
16. Duong LT, Lakkakorpi PT, Nakamura I, Machwate M, Nagy RM, Rodan GA
    PYK2 in osteoclasts is an adhesion kinase, localized in the sealing zone, activated by ligation of alpha(v)beta3 integrin, and phosphorylated by src kinase. The Journal of clinical investigation 1998 Sep 1;102(5):881-92
17. Lakkakorpi PT, Nakamura I, Nagy RM, Parsons JT, Rodan GA, Duong LT
    Stable association of PYK2 and p130(Cas) in osteoclasts and their co-localization in the sealing zone. The Journal of biological chemistry 1999 Feb 19;274(8):4900-7
18. Chellaiah MA, Kizer N, Biswas R, Alvarez U, Strauss-Schoenberger J, Rifas L, Rittling SR, Denhardt DT, Hruska KA
    Osteopontin deficiency produces osteoclast dysfunction due to reduced CD44 surface expression. Molecular biology of the cell 2003 Jan;14(1):173-89