A PDGFRβ-PI3K signaling axis mediates periosteal cell activation during fracture healing


Autoři: Laura Doherty aff001;  Jungeun Yu aff001;  Xi Wang aff002;  Kurt D. Hankenson aff003;  Ivo Kalajzic aff002;  Archana Sanjay aff001
Působiště autorů: Department of Orthopaedic Surgery, UConn Health, Farmington, Connecticut, United States of America aff001;  Department of Reconstructive Sciences, UConn Health, Farmington, Connecticut, United States of America aff002;  Department of Orthopaedic Surgery, School of Medicine, University of Michigan, Ann Arbor, Michigan, United States of America aff003
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: 10.1371/journal.pone.0223846

Souhrn

Insufficient and delayed fracture healing remain significant public health problems with limited therapeutic options. Phosphoinositide 3-kinase (PI3K) signaling, a major pathway involved in regulation of fracture healing, promotes proliferation, migration, and differentiation of osteoprogenitors. We have recently reported that knock-in mice with a global increase in PI3K signaling (gCblYF) show enhanced femoral fracture healing characterized by an extraordinary periosteal response to injury. Interestingly, of all growth factor receptors involved in fracture healing, PI3K directly binds only to PDGFR. Given these findings, we hypothesized a PDGFR-PI3K interaction is necessary for mediating robust periosteal cell activation following fracture. In this study, we isolated primary periosteal cells from gCblYF mice to analyze cross-talk between the PDGFRβ and PI3K signaling pathways. We found PDGFRβ signaling contributes to robust Akt phosphorylation in periosteal cells in comparison with other growth factor signaling pathways. Additionally, we performed femoral fractures on gCblYF mice with a conditional removal of PDGFRβ in mesenchymal progenitors using inducible alpha smooth muscle actin (αSMA) CreERT2 mice. Our studies showed that depletion of PDGFRβ signaling within these progenitors in the early phase of fracture healing significantly abrogates PI3K-mediated periosteal activation and proliferation three days after fracture. Combined, these results suggest that PDGFRβ signaling through PI3K is necessary for robust periosteal activation in the earliest phases of fracture healing.

Klíčová slova:

Bone fracture – Cell staining – Femur – Flow cytometry – Growth factors – Mouse models – Tissue repair – Periosteum


Zdroje

1. Hadjiargyrou M, O’Keefe RJ (2014) The convergence of fracture repair and stem cells: interplay of genes, aging, environmental factors and disease. J Bone Miner Res 29:2307–2322 doi: 10.1002/jbmr.2373 25264148

2. Claes L, Recknagel S, Ignatius A (2012) Fracture healing under healthy and inflammatory conditions. Nat Rev Rheumatol 8:133–143 doi: 10.1038/nrrheum.2012.1 22293759

3. Parker MJ, Raghavan R, Gurusamy K (2007) Incidence of fracture-healing complications after femoral neck fractures. Clin Orthop Relat Res 458:175–179 17224836

4. Paino F, La Noce M, Giuliani A, De Rosa A, Mazzoni S, Laino L, Amler E, Papaccio G, Desiderio V, Tirino V (2017) Human DPSCs fabricate vascularized woven bone tissue: a new tool in bone tissue engineering. Clin Sci (Lond) 131:699–713

5. Su P, Tian Y, Yang C, Ma X, Wang X, Pei J, Qian A (2018) Mesenchymal Stem Cell Migration during Bone Formation and Bone Diseases Therapy. Int J Mol Sci 19

6. Bianco P, Riminucci M, Gronthos S, Robey PG (2001) Bone marrow stromal stem cells: nature, biology, and potential applications. Stem Cells 19:180–192 doi: 10.1634/stemcells.19-3-180 11359943

7. Colnot C (2009) Skeletal cell fate decisions within periosteum and bone marrow during bone regeneration. Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 24:274–282

8. Colnot C, Zhang X, Knothe Tate ML (2012) Current insights on the regenerative potential of the periosteum: molecular, cellular, and endogenous engineering approaches. Journal of orthopaedic research: official publication of the Orthopaedic Research Society 30:1869–1878

9. Cantley LC (2002) The phosphoinositide 3-kinase pathway. Science 296:1655–1657 doi: 10.1126/science.296.5573.1655 12040186

10. Mukherjee A, Wilson EM, Rotwein P (2010) Selective signaling by Akt2 promotes bone morphogenetic protein 2-mediated osteoblast differentiation. Mol. Cell. Biol. 30:1018–1027 doi: 10.1128/MCB.01401-09 19995912

11. Reusch HP, Zimmermann S, Schaefer M, Paul M, Moelling K (2001) Regulation of Raf by Akt controls growth and differentiation in vascular smooth muscle cells. J. Biol. Chem. 276:33630–33637 doi: 10.1074/jbc.M105322200 11443134

12. Ulici V, Hoenselaar KD, Agoston H, McErlain DD, Umoh J, Chakrabarti S, Holdsworth DW, Beier F (2009) The role of Akt1 in terminal stages of endochondral bone formation: angiogenesis and ossification. Bone 45:1133–1145 doi: 10.1016/j.bone.2009.08.003 19679212

13. Guntur AR, Rosen CJ (2011) The skeleton: a multi-functional complex organ: new insights into osteoblasts and their role in bone formation: the central role of PI3Kinase. J Endocrinol 211:123–130 doi: 10.1530/JOE-11-0175 21673026

14. Scanlon V, Walia B, Yu J, Hansen M, Drissi H, Maye P, Sanjay A (2017) Loss of Cbl-PI3K interaction modulates the periosteal response to fracture by enhancing osteogenic commitment and differentiation. Bone 95:124–135 doi: 10.1016/j.bone.2016.11.020 27884787

15. Hung BP, Hutton DL, Kozielski KL, Bishop CJ, Naved B, Green JJ, Caplan AI, Gimble JM, Dorafshar AH, Grayson WL (2015) Platelet-Derived Growth Factor BB Enhances Osteogenesis of Adipose-Derived But Not Bone Marrow-Derived Mesenchymal Stromal/Stem Cells. Stem Cells 33:2773–2784 doi: 10.1002/stem.2060 26013357

16. Mehrotra M, Krane SM, Walters K, Pilbeam C (2004) Differential regulation of platelet-derived growth factor stimulated migration and proliferation in osteoblastic cells. J Cell Biochem 93:741–752 doi: 10.1002/jcb.20138 15660418

17. Tokunaga A, Oya T, Ishii Y, Motomura H, Nakamura C, Ishizawa S, Fujimori T, Nabeshima Y, Umezawa A, Kanamori M, Kimura T, Sasahara M (2008) PDGF receptor beta is a potent regulator of mesenchymal stromal cell function. J Bone Miner Res 23:1519–1528 doi: 10.1359/jbmr.080409 18410236

18. Friedlaender GE, Lin S, Solchaga LA, Snel LB, Lynch SE (2013) The role of recombinant human platelet-derived growth factor-BB (rhPDGF-BB) in orthopaedic bone repair and regeneration. Curr Pharm Des 19:3384–3390 doi: 10.2174/1381612811319190005 23432673

19. Graham S, Leonidou A, Lester M, Heliotis M, Mantalaris A, Tsiridis E (2009) Investigating the role of PDGF as a potential drug therapy in bone formation and fracture healing. Expert Opinion on Investigational Drugs 18:1633–1654 doi: 10.1517/13543780903241607 19747084

20. Wang X, Matthews BG, Yu J, Novak S, Grcevic D, Sanjay A, Kalajzic I (2019) PDGF Modulates BMP2-Induced Osteogenesis in Periosteal Progenitor Cells. JBMR Plus 3:e10127 doi: 10.1002/jbm4.10127 31131345

21. Fantauzzo KA, Soriano P (2014) PI3K-mediated PDGFRalpha signaling regulates survival and proliferation in skeletal development through p53-dependent intracellular pathways. Genes Dev 28:1005–1017 doi: 10.1101/gad.238709.114 24788519

22. Klinghoffer RA, Hamilton TG, Hoch R, Soriano P (2002) An allelic series at the PDGFalphaR locus indicates unequal contributions of distinct signaling pathways during development. Dev Cell 2:103–113 11782318

23. Molotkov A, Soriano P (2018) Distinct mechanisms for PDGF and FGF signaling in primitive endoderm development. Dev Biol 442:155–161 doi: 10.1016/j.ydbio.2018.07.010 30026121

24. Ueno H, Sasaki K, Honda H, Nakamoto T, Yamagata T, Miyagawa K, Mitani K, Yazaki Y, Hirai H (1998) c-Cbl is tyrosine-phosphorylated by interleukin-4 and enhances mitogenic and survival signals of interleukin-4 receptor by linking with the phosphatidylinositol 3'-kinase pathway. Blood 91:46–53 9414268

25. Molero JC, Turner N, Thien CB, Langdon WY, James DE, Cooney GJ (2006) Genetic ablation of the c-Cbl ubiquitin ligase domain results in increased energy expenditure and improved insulin action. Diabetes 55:3411–3417 doi: 10.2337/db06-0955 17130487

26. Adapala NS, Barbe MF, Langdon WY, Nakamura MC, Tsygankov AY, Sanjay A (2010) The loss of Cbl-phosphatidylinositol 3-kinase interaction perturbs RANKL-mediated signaling, inhibiting bone resorption and promoting osteoclast survival. J. Biol. Chem. 285:36745–36758 doi: 10.1074/jbc.M110.124628 20851882

27. Adapala NS, Barbe MF, Tsygankov AY, Lorenzo JA, Sanjay A (2014) Loss of Cbl-PI3K interaction enhances osteoclast survival due to p21-Ras mediated PI3K activation independent of Cbl-b. Journal of cellular biochemistry 115:1277–1289 doi: 10.1002/jcb.24779 24470255

28. Brennan T, Adapala NS, Barbe MF, Yingling V, Sanjay A (2011) Abrogation of Cbl-PI3K interaction increases bone formation and osteoblast proliferation. Calcified tissue international 89:396–410 doi: 10.1007/s00223-011-9531-z 21952831

29. Scanlon V, Soung do Y, Adapala NS, Morgan E, Hansen MF, Drissi H, Sanjay A (2015) Role of Cbl-PI3K Interaction during Skeletal Remodeling in a Murine Model of Bone Repair. PLoS One 10:e0138194 doi: 10.1371/journal.pone.0138194 26393915

30. Adapala Naga Suresh B MF, T AY, L JA, Sanjay Archana (2014) Loss of Cbl–PI3K Interaction Enhances Osteoclast Survival due to p21-Ras Mediated PI3K Activation Independent of Cbl-b. Journal of Cellular Biochemistry 1:1–13

31. Wu E, Palmer N, Tian Z, Moseman AP, Galdzicki M, Wang X, Berger B, Zhang H, Kohane IS (2008) Comprehensive dissection of PDGF-PDGFR signaling pathways in PDGFR genetically defined cells. PLoS One 3:e3794 doi: 10.1371/journal.pone.0003794 19030102

32. Gong YQ, Huang W, Li KR, Liu YY, Cao GF, Cao C, Jiang Q (2016) SC79 protects retinal pigment epithelium cells from UV radiation via activating Akt-Nrf2 signaling. Oncotarget 7:60123–60132 doi: 10.18632/oncotarget.11164 27517753

33. Jo H, Mondal S, Tan D, Nagata E, Takizawa S, Sharma AK, Hou Q, Shanmugasundaram K, Prasad A, Tung JK, Tejeda AO, Man H, Rigby AC, Luo HR (2012) Small molecule-induced cytosolic activation of protein kinase Akt rescues ischemia-elicited neuronal death. Proc Natl Acad Sci U S A 109:10581–10586 doi: 10.1073/pnas.1202810109 22689977

34. Grcevic D, Pejda S, Matthews BG, Repic D, Wang L, Li H, Kronenberg MS, Jiang X, Maye P, Adams DJ, Rowe DW, Aguila HL, Kalajzic I (2012) In vivo fate mapping identifies mesenchymal progenitor cells. Stem cells 30:187–196 doi: 10.1002/stem.780 22083974

35. Matthews BG, Grcevic D, Wang L, Hagiwara Y, Roguljic H, Joshi P, Shin D-G, Adams DJ, Kalajzic I (2014) Analysis of αSMA-labeled progenitor cell commitment identifies notch signaling as an important pathway in fracture healing. J. Bone Miner. Res. 29:1283–1294 doi: 10.1002/jbmr.2140 24190076

36. Majidinia M, Sadeghpour A, Yousefi B (2018) The roles of signaling pathways in bone repair and regeneration. J Cell Physiol 233:2937–2948 doi: 10.1002/jcp.26042 28590066

37. Burgers TA, Hoffmann MF, Collins CJ, Zahatnansky J, Alvarado MA, Morris MR, Sietsema DL, Mason JJ, Jones CB, Ploeg HL, Williams BO (2013) Mice lacking pten in osteoblasts have improved intramembranous and late endochondral fracture healing. PloS one 8:e63857 doi: 10.1371/journal.pone.0063857 23675511

38. W Xi, M B.G., Yu J., Novack S., Grevic D., Sanjay A., Kalajzic I (2018) PDGF modulates BMP2 induced osteogenesis in periosteal progenitor cells. JBMR Plus In Press

39. Matthews BG, Grcevic D, Wang L, Hagiwara Y, Roguljic H, Joshi P, Shin D-G, Adams DJ, Kalajzic I (2014) Analysis of αSMA-Labeled Progenitor Cell Commitment Identifies Notch Signaling as an Important Pathway in Fracture Healing: αSMA-EXPRESSING MESENCHYMAL PROGENITOR CELLS IN FRACTURE HEALING. Journal of Bone and Mineral Research 29:1283–1294 doi: 10.1002/jbmr.2140 24190076

40. Youngstrom DW, Senos R, Zondervan RL, Brodeur JD, Lints AR, Young DR, Mitchell TL, Moore ME, Myers MH, Tseng W-J, Loomes KM, Hankenson KD (2017) Intraoperative delivery of the Notch ligand Jagged-1 regenerates appendicular and craniofacial bone defects. npj Regenerative Medicine 2.

41. Andrae J, Gallini R, Betsholtz C (2008) Role of platelet-derived growth factors in physiology and medicine. Genes Dev 22:1276–1312 doi: 10.1101/gad.1653708 18483217

42. Schmahl J, Rizzolo K, Soriano P (2008) The PDGF signaling pathway controls multiple steroid-producing lineages. Genes Dev 22:3255–3267 doi: 10.1101/gad.1723908 19056881

43. He C, Medley SC, Hu T, Hinsdale ME, Lupu F, Virmani R, Olson LE (2015) PDGFRbeta signalling regulates local inflammation and synergizes with hypercholesterolaemia to promote atherosclerosis. Nat Commun 6:7770 doi: 10.1038/ncomms8770 26183159

44. Olson LE, Soriano P (2011) PDGFRbeta signaling regulates mural cell plasticity and inhibits fat development. Dev Cell 20:815–826 doi: 10.1016/j.devcel.2011.04.019 21664579

45. Mele L, Vitiello PP, Tirino V, Paino F, De Rosa A, Liccardo D, Papaccio G, Desiderio V (2016) Changing Paradigms in Cranio-Facial Regeneration: Current and New Strategies for the Activation of Endogenous Stem Cells. Front Physiol 7:62 doi: 10.3389/fphys.2016.00062 26941656

46. Paglia DN, Singh H, Karukonda T, Drissi H, Moss IL (2016) PDGF-BB Delays Degeneration of the Intervertebral Discs in a Rabbit Preclinical Model. SPINE 41:E449–E458 doi: 10.1097/BRS.0000000000001336 27064336

47. Li G, Wang L, Jiang Y, Kong X, Fan Q, Ge S, Hao Y (2017) Upregulation of Akt signaling enhances femoral fracture healing by accelerating atrophic quadriceps recovery. Biochim Biophys Acta 1863:2848–2861

48. Murao H, Yamamoto K, Matsuda S, Akiyama H (2013) Periosteal cells are a major source of soft callus in bone fracture. J Bone Miner Metab 31:390–398 doi: 10.1007/s00774-013-0429-x 23475152


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