Protein tyrosine phosphatases in skeletal development and diseases

Abstract

Skeletal development and homeostasis in mammals are modulated by finely coordinated processes of migration, proliferation, differentiation, and death of skeletogenic cells originating from the mesoderm and neural crest. Numerous molecular mechanisms are involved in these regulatory processes, one of which is protein posttranslational modifications, particularly protein tyrosine phosphorylation (PYP). PYP occurs mainly through the action of protein tyrosine kinases (PTKs), modifying protein enzymatic activity, changing its cellular localization, and aiding in the assembly or disassembly of protein signaling complexes. Under physiological conditions, PYP is balanced by the coordinated action of PTKs and protein tyrosine phosphatases (PTPs). Dysregulation of PYP can cause genetic, metabolic, developmental, and oncogenic skeletal diseases. Although PYP is a reversible biochemical process, in contrast to PTKs, little is known about how this equilibrium is modulated by PTPs in the skeletal system. Whole-genome sequencing has revealed a large and diverse superfamily of PTP genes (over 100 members) in humans, which can be further divided into cysteine (Cys)-, aspartic acid (Asp)-, and histidine (His)-based PTPs. Here, we review current knowledge about the functions and regulatory mechanisms of 28 PTPs involved in skeletal development and diseases; 27 of them belong to class I and II Cys-based PTPs, and the other is an Asp-based PTP. Recent progress in analyzing animal models that harbor various mutations in these PTPs and future research directions are also discussed. Our literature review indicates that PTPs are as crucial as PTKs in supporting skeletal development and homeostasis.

References

[1] Olsen BR, Reginato AM, Wang W. Bone development. Annu. Rev. Cell Dev. Biol., 2000, 16: 191-220

[2] Ornitz DM, Marie PJ. Fibroblast growth factors in skeletal development. Curr. Top. Dev. Biol., 2019, 133: 195-234

[3] Bohm AM et al. Activation of skeletal stem and progenitor cells for bone regeneration is driven by PDGFRbeta Signaling. Dev. Cell, 2019, 51: 236-254.e212

[4] Sivaraj KK, Adams RH. Blood vessel formation and function in bone. Development, 2016, 143: 2706-2715

[5] Zhu J, Shimizu E, Zhang X, Partridge NC, Qin L. EGFR signaling suppresses osteoblast differentiation and inhibits expression of master osteoblastic transcription factors Runx2 and Osterix. J. Cell Biochem., 2011, 112: 1749-1760

[6] Kaneshiro S et al. IL-6 negatively regulates osteoblast differentiation through the SHP2/MEK2 and SHP2/Akt2 pathways in vitro. J. Bone Miner. Metab., 2014, 32: 378-392

[7] Colognato H, Ramachandrappa S, Olsen IM, ffrench-Constant C. Integrins direct Src family kinases to regulate distinct phases of oligodendrocyte development. J. Cell Biol., 2004, 167: 365-375

[8] Ichinohe T et al. Collagen-stimulated activation of Syk but not c-Src is severely compromised in human platelets lacking membrane glycoprotein VI. J. Biol. Chem., 1997, 272: 63-68

[9] Tzeng YS et al. Imbalanced osteogenesis and adipogenesis in mice deficient in the chemokine Cxcl12/Sdf1 in the bone mesenchymal stem/progenitor cells. J. Bone Miner. Res., 2018, 33: 679-690

[10] Dikic I, Tokiwa G, Lev S, Courtneidge SA, Schlessinger J. A role for Pyk2 and Src in linking G-protein-coupled receptors with MAP kinase activation. Nature, 1996, 383: 547-550

[11] McDonell LM, Kernohan KD, Boycott KM, Sawyer SL. Receptor tyrosine kinase mutations in developmental syndromes and cancer: two sides of the same coin. Hum. Mol. Genet., 2015, 24: R60-R66

[12] Xu X et al. Transforming growth factor-beta in stem cells and tissue homeostasis. Bone Res., 2018, 6: 2

[13] Yang W et al. Ptpn11 deletion in a novel progenitor causes metachondromatosis by inducing hedgehog signalling. Nature, 2013, 499: 491-495

[14] Alonso A, Pulido R. The extended human PTPome: a growing tyrosine phosphatase family. FEBS J., 2016, 283: 2197-2201

[15] Tonks NK. Protein tyrosine phosphatases: from genes, to function, to disease. Nat. Rev. Mol. Cell Biol., 2006, 7: 833-846

[16] Alonso A et al. Protein tyrosine phosphatases in the human genome. Cell, 2004, 117: 699-711

[17] Martell KJ, Angelotti T, Ullrich A. The “VH1-like” dual-specificity protein tyrosine phosphatases. Mol. Cells, 1998, 8: 2-11

[18] Andersen JN et al. A genomic perspective on protein tyrosine phosphatases: gene structure, pseudogenes, and genetic disease linkage. FASEB J., 2004, 18: 8-30

[19] Long F, Ornitz DM. Development of the endochondral skeleton. Cold Spring Harb. Perspect. Biol., 2013, 5: a008334

[20] Salazar VS, Gamer LW, Rosen V. BMP signalling in skeletal development, disease and repair. Nat. Rev. Endocrinol., 2016, 12: 203-221

[21] Karsenty G, Kronenberg HM, Settembre C. Genetic control of bone formation. Annu. Rev. Cell Dev. Biol., 2009, 25: 629-648

[22] Rutkovskiy A, Stenslokken KO, Vaage IJ. Osteoblast differentiation at a glance. Med. Sci. Monit. Basic Res., 2016, 22: 95-106

[23] Wang L et al. SHP2 regulates the osteogenic fate of growth plate hypertrophic chondrocytes. Sci. Rep., 2017, 7

[24] Yang L, Tsang KY, Tang HC, Chan D, Cheah KS. Hypertrophic chondrocytes can become osteoblasts and osteocytes in endochondral bone formation. Proc. Natl Acad. Sci. USA, 2014, 111: 12097-12102

[25] Stewart K, Uetani N, Hendriks W, Tremblay ML, Bouchard M. Inactivation of LAR family phosphatase genes Ptprs and Ptprf causes craniofacial malformations resembling Pierre-Robin sequence. Development, 2013, 140: 3413-3422

[26] Hendriks WJ et al. Protein tyrosine phosphatases in health and disease. FEBS J., 2013, 280: 708-730

[27] Chagnon MJ, Uetani N, Tremblay ML. Functional significance of the LAR receptor protein tyrosine phosphatase family in development and diseases. Biochem. Cell Biol., 2004, 82: 664-675

[28] Izumi K, Konczal LL, Mitchell AL, Jones MC. Underlying genetic diagnosis of Pierre Robin sequence: retrospective chart review at two children’s hospitals and a systematic literature review. J. Pediatr., 2012, 160: 645-650 e642

[29] Kim WK et al. Regulation of adipogenic differentiation by LAR tyrosine phosphatase in human mesenchymal stem cells and 3T3-L1 preadipocytes. J. Cell Sci., 2009, 122: 4160-4167

[30] Kim WK et al. Leukocyte common antigen-related (LAR) tyrosine phosphatase positively regulates osteoblast differentiation by modulating extracellular signal-regulated kinase (ERK) activation. Mol. Cells, 2010, 30: 335-340

[31] Kim JM et al. The ERK MAPK pathway is essential for skeletal development and homeostasis. Int. J. Mol. Sci., 2019, 20: 1803

[32] Matsushita T et al. Extracellular signal-regulated kinase 1 (ERK1) and ERK2 play essential roles in osteoblast differentiation and in supporting osteoclastogenesis. Mol. Cell Biol., 2009, 29: 5843-5857

[33] Franceschi RT, Ge C. Control of the osteoblast lineage by mitogen-activated protein kinase signaling. Curr. Mol. Biol. Rep., 2017, 3: 122-132

[34] Mundlos S et al. Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia. Cell, 1997, 89: 773-779

[35] Mundlos S. Cleidocranial dysplasia: clinical and molecular genetics. J. Med. Genet., 1999, 36: 177-182

[36] Zuo C et al. SHP2 regulates skeletal cell fate by modifying SOX9 expression and transcriptional activity. Bone Res., 2018, 6: 12

[37] Lapinski PE, Meyer MF, Feng GS, Kamiya N, King PD. Deletion of SHP-2 in mesenchymal stem cells causes growth retardation, limb and chest deformity and calvarial defects in mice. Dis. Model Mech., 2013, 6: 1448-1458

[38] Wang L et al. Targeted Ptpn11 deletion in mice reveals the essential role of SHP2 in osteoblast differentiation and skeletal homeostasis. Bone Res., 2021, 9: 6

[39] Pallen CJ. Protein tyrosine phosphatase alpha (PTPalpha): a Src family kinase activator and mediator of multiple biological effects. Curr. Top. Med. Chem., 2003, 3: 821-835

[40] Kaplan R et al. Cloning of three human tyrosine phosphatases reveals a multigene family of receptor-linked protein-tyrosine-phosphatases expressed in brain. Proc. Natl Acad. Sci. USA, 1990, 87: 7000-7004

[41] Lezcano V, Bellido T, Plotkin LI, Boland R, Morelli S. Osteoblastic protein tyrosine phosphatases inhibition and connexin 43 phosphorylation by alendronate. Exp. Cell Res., 2014, 324: 30-39

[42] Morelli S et al. Protein phosphatases: possible bisphosphonate binding sites mediating stimulation of osteoblast proliferation. Arch. Biochem. Biophys., 2011, 507: 248-253

[43] Plotkin LI et al. Prevention of osteocyte and osteoblast apoptosis by bisphosphonates and calcitonin. J. Clin. Investig., 1999, 104: 1363-1374

[44] Koop EA et al. Receptor protein tyrosine phosphatase mu expression as a marker for endothelial cell heterogeneity; analysis of RPTPmu gene expression using LacZ knock-in mice. Int. J. Dev. Biol., 2003, 47: 345-354

[45] Kim WK et al. RPTPmu tyrosine phosphatase promotes adipogenic differentiation via modulation of p120 catenin phosphorylation. Mol. Biol. Cell, 2011, 22: 4883-4891

[46] de Rooij KE et al. Identification of receptor-type protein tyrosine phosphatase mu as a new marker for osteocytes. Histochem. Cell Biol., 2015, 144: 1-11

[47] Baldauf C et al. The protein tyrosine phosphatase Rptpzeta suppresses osteosarcoma development in Trp53-Heterozygous mice. PLoS One, 2015, 10: e0137745

[48] Maeda Y, Schipani E, Densmore MJ, Lanske B. Partial rescue of postnatal growth plate abnormalities in Ihh mutants by expression of a constitutively active PTH/PTHrP receptor. Bone, 2010, 46: 472-478

[49] Schiller KR, Mauro LJ. Tyrosine phosphatases as regulators of skeletal development and metabolism. J. Cell Biochem., 2005, 96: 262-277

[50] Schinke T et al. The protein tyrosine phosphatase Rptpzeta is expressed in differentiated osteoblasts and affects bone formation in mice. Bone, 2008, 42: 524-534

[51] Qi M et al. Haptotactic migration induced by midkine. Involvement of protein-tyrosine phosphatase zeta. Mitogen-activated protein kinase, and phosphatidylinositol 3-kinase. J. Biol. Chem., 2001, 276: 15868-15875

[52] Meng K et al. Pleiotrophin signals increased tyrosine phosphorylation of beta beta-catenin through inactivation of the intrinsic catalytic activity of the receptor-type protein tyrosine phosphatase beta/zeta. Proc. Natl Acad. Sci. USA, 2000, 97: 2603-2608

[53] Chengalvala MV et al. Biochemical characterization of osteo-testicular protein tyrosine phosphatase and its functional significance in rat primary osteoblasts. Biochemistry, 2001, 40: 814-821

[54] Dacquin R et al. Knock-in of nuclear localised beta-galactosidase reveals that the tyrosine phosphatase Ptprv is specifically expressed in cells of the bone collar. Dev. Dyn., 2004, 229: 826-834

[55] Wheeler MA, Townsend MK, Yunker LA, Mauro LJ. Transcriptional activation of the tyrosine phosphatase gene, OST-PTP, during osteoblast differentiation. J. Cell Biochem., 2002, 87: 363-376

[56] Yunker LA et al. The tyrosine phosphatase, OST-PTP, is expressed in mesenchymal progenitor cells early during skeletogenesis in the mouse. J. Cell Biochem., 2004, 93: 761-773

[57] Ng KW. Regulation of glucose metabolism and the skeleton. Clin. Endocrinol., 2011, 75: 147-155

[58] Ferron M et al. Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism. Cell, 2010, 142: 296-308

[59] Lee NK et al. Endocrine regulation of energy metabolism by the skeleton. Cell, 2007, 130: 456-469

[60] Tonks NK. PTP1B: from the sidelines to the front lines!. FEBS Lett., 2003, 546: 140-148

[61] Tonks NK. Protein tyrosine phosphatases–from housekeeping enzymes to master regulators of signal transduction. FEBS J., 2013, 280: 346-378

[62] Frangioni JV, Beahm PH, Shifrin V, Jost CA, Neel BG. The nontransmembrane tyrosine phosphatase PTP-1B localizes to the endoplasmic reticulum via its 35 amino acid C-terminal sequence. Cell, 1992, 68: 545-560

[63] Elchebly M et al. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science, 1999, 283: 1544-1548

[64] Klaman LD et al. Increased energy expenditure, decreased adiposity, and tissue-specific insulin sensitivity in protein-tyrosine phosphatase 1B-deficient mice. Mol. Cell Biol., 2000, 20: 5479-5489

[65] Yang J, Zhang X, Wang W, Liu J. Insulin stimulates osteoblast proliferation and differentiation through ERK and PI3K in MG-63 cells. Cell Biochem. Funct., 2010, 28: 334-341

[66] Bandyopadhyay D et al. Protein-tyrosine phosphatase 1B complexes with the insulin receptor in vivo and is tyrosine-phosphorylated in the presence of insulin. J. Biol. Chem., 1997, 272: 1639-1645

[67] Goldstein BJ, Bittner-Kowalczyk A, White MF, Harbeck M. Tyrosine dephosphorylation and deactivation of insulin receptor substrate-1 by protein-tyrosine phosphatase 1B. Possible facilitation by the formation of a ternary complex with the Grb2 adaptor protein. J. Biol. Chem., 2000, 275: 4283-4289

[68] Rossi MC et al. Titanium-released from dental implant enhances pre-osteoblast adhesion by ROS modulating crucial intracellular pathways. J. Biomed. Mater. Res. Part A, 2017, 105: 2968-2976

[69] Neel, B. G., Chan, G. & Dhanji, S. SH2 domain-containing protein-tyrosine phosphatases. Handbook of Cell Signal. 2nd edn, Vol. 2, (Bradshaw, R. A. & Dennis, E. A.) Ch. 98 (Oxford Academic Press, 2009).

[70] Green MC, Shultz LD. Motheaten, an immunodeficient mutant of the mouse. I. Genetics and pathology. J. Hered., 1975, 66: 250-258

[71] Tsui FW, Tsui HW. Molecular basis of the motheaten phenotype. Immunol. Rev., 1994, 138: 185-206

[72] Jiang M et al. SHP1 regulates bone mass by directing mesenchymal stem cell differentiation. Cell Rep., 2016, 17: 2161

[73] Tang XL, Wang CN, Zhu XY, Ni X. Protein tyrosine phosphatase SHP-1 modulates osteoblast differentiation through direct association with and dephosphorylation of GSK3beta. Mol. Cell. Endocrinol., 2017, 439: 203-212

[74] Aoki K et al. The tyrosine phosphatase SHP-1 is a negative regulator of osteoclastogenesis and osteoclast resorbing activity: increased resorption and osteopenia in me(v)/me(v) mutant mice. Bone, 1999, 25: 261-267

[75] Umeda S et al. Deficiency of SHP-1 protein-tyrosine phosphatase activity results in heightened osteoclast function and decreased bone density. Am. J. Pathol., 1999, 155: 223-233

[76] Rangaswami H et al. Cyclic GMP and protein kinase G control a Src-containing mechanosome in osteoblasts. Sci. Signal., 2010, 3: ra91

[77] Zhang SQ et al. Shp2 regulates SRC family kinase activity and Ras/Erk activation by controlling Csk recruitment. Mol. Cell, 2004, 13: 341-355

[78] Saxton T et al. Abnormal mesoderm patterning in mouse embryos mutant for the SH2 tyrosine phosphatase Shp-2. EMBO J., 1997, 16: p2352-p2364

[79] Yang W et al. An Shp2/SFK/Ras/Erk signaling pathway controls trophoblast stem cell survival. Dev. Cell, 2006, 10: 317-327

[80] Choudhry KS et al. Decreased bone mineralization in children with Noonan syndrome: another consequence of dysregulated RAS MAPKinase pathway? Mol. Genet. Metab., 2012, 106: 237-240

[81] Baldassarre G, Mussa A, Carli D, Molinatto C, Ferrero GB. Constitutional bone impairment in Noonan syndrome. Am. J. Med. Genet. A, 2017, 173: 692-698

[82] Roberts AE, Allanson JE, Tartaglia M, Gelb BD. Noonan syndrome. Lancet, 2013, 381: 333-342

[83] Tartaglia M et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am. J. Hum. Genet., 2002, 70: 1555-1563

[84] Wang L et al. SHP2 regulates intramembranous ossification by modifying the TGFbeta and BMP2 signaling pathway. Bone, 2019, 120: 327-335

[85] Kyono A, Avishai N, Ouyang Z, Landreth GE, Murakami S. FGF and ERK signaling coordinately regulate mineralization-related genes and play essential roles in osteocyte differentiation. J. Bone Miner. Metab., 2012, 30: 19-30

[86] Kawamura N et al. Akt1 in osteoblasts and osteoclasts controls bone remodeling. PLoS One, 2007, 2: e1058

[87] Mukherjee A, Wilson EM, Rotwein P. Selective signaling by Akt2 promotes bone morphogenetic protein 2-mediated osteoblast differentiation. Mol. Cell Biol., 2010, 30: 1018-1027

[88] Zhou H et al. Osteoblast/osteocyte-specific inactivation of Stat3 decreases load-driven bone formation and accumulates reactive oxygen species. Bone, 2011, 49: 404-411

[89] Corry KA et al. Stat3 in osteocytes mediates osteogenic response to loading. Bone Rep., 2019, 11: 100218

[90] Ohtani T et al. Dissection of signaling cascades through gp130 in vivo: reciprocal roles for STAT3- and SHP2-mediated signals in immune responses. Immunity, 2000, 12: 95-105

[91] Atsumi T et al. A point mutation of Tyr-759 in interleukin 6 family cytokine receptor subunit gp130 causes autoimmune arthritis. J. Exp. Med., 2002, 196: 979-990

[92] Ornitz DM, Marie PJ. FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease. Genes Dev., 2002, 16: 1446-1465

[93] Saxton TM et al. The SH2 tyrosine phosphatase shp2 is required for mammalian limb development. Nat. Genet., 2000, 24: 420-423

[94] Mansukhani A, Bellosta P, Sahni M, Basilico C. Signaling by fibroblast growth factors (FGF) and fibroblast growth factor receptor 2 (FGFR2)-activating mutations blocks mineralization and induces apoptosis in osteoblasts. J. Cell Biol., 2000, 149: 1297-1308

[95] Sahni M, Raz R, Coffin JD, Levy D, Basilico C. STAT1 mediates the increased apoptosis and reduced chondrocyte proliferation in mice overexpressing FGF2. Development, 2001, 128: 2119-2129

[96] Fan D et al. The use of SHP-2 gene transduced bone marrow mesenchymal stem cells to promote osteogenic differentiation and bone defect repair in rat. J. Biomed. Mater. Res. Part A, 2016, 104: 1871-1881

[97] Zhou RP et al. Chlorogenic acid prevents osteoporosis by Shp2/PI3K/Akt pathway in ovariectomized rats. PLoS One, 2016, 11: e0166751

[98] Zheng Y, Lu Z. Regulation of tumor cell migration by protein tyrosine phosphatase (PTP)-proline-, glutamate-, serine-,and threonine-rich sequence (PEST). Chin. J. Cancer, 2013, 32: 75-83

[99] Yang Q, Co D, Sommercorn J, Tonks NK. Cloning and expression of PTP-PEST. A novel, human, nontransmembrane protein tyrosine phosphatase. J. Biol. Chem., 1993, 268: 17650

[100] Charest A, Wagner J, Muise ES, Heng HH, Tremblay ML. Structure of the murine MPTP-PEST gene: genomic organization and chromosomal mapping. Genomics, 1995, 28: 501-507

[101] Eleniste PP, Huang S, Wayakanon K, Largura HW, Bruzzaniti A. Osteoblast differentiation and migration are regulated by dynamin GTPase activity. Int. J. Biochem. Cell Biol., 2014, 46: 9-18

[102] Matsushita, T., Murakami S. The ERK MAPK Pathway in Bone and Cartilage Formation. ISBN: 978-953-51-0640-1. InTech (2012).

[103] Broome DT, Datta NS. Mitogen-activated protein kinase phosphatase-1: function and regulation in bone and related tissues. Connect. Tissue Res., 2016, 57: 175-189

[104] Mahalingam CD et al. Mitogen-activated protein kinase phosphatase 1 regulates bone mass, osteoblast gene expression, and responsiveness to parathyroid hormone. J. Endocrinol., 2011, 211: 145-156

[105] Mahalingam CD et al. MKP1-dependent PTH modulation of bone matrix mineralization in female mice is osteoblast maturation stage specific and involves P-ERK and P-p38 MAPKs. J. Endocrinol., 2013, 216: 315-329

[106] Ghayor C, Ehrbar M, San Miguel B, Gratz KW, Weber FE. cAMP enhances BMP2-signaling through PKA and MKP1-dependent mechanisms. Biochem. Biophys. Res. Commun., 2009, 381: 247-252

[107] Phillips JE, Gersbach CA, Wojtowicz AM, Garcia AJ. Glucocorticoid-induced osteogenesis is negatively regulated by Runx2/Cbfa1 serine phosphorylation. J. Cell Sci., 2006, 119: 581-591

[108] Suttamanatwong S, Franceschi RT, Carlson AE, Gopalakrishnan R. Regulation of matrix Gla protein by parathyroid hormone in MC3T3-E1 osteoblast-like cells involves protein kinase A and extracellular signal-regulated kinase pathways. J. Cell Biochem., 2007, 102: 496-505

[109] Steck PA et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat. Genet., 1997, 15: 356-362

[110] Worby CA, Dixon JE. Pten. Annu. Rev. Biochem., 2014, 83: 641-669

[111] Di Cristofano A, Pesce B, Cordon-Cardo C, Pandolfi PP. Pten is essential for embryonic development and tumour suppression. Nat. Genet., 1998, 19: 348-355

[112] Stambolic V et al. High incidence of breast and endometrial neoplasia resembling human Cowden syndrome in pten^+/− mice. Cancer Res., 2000, 60: 3605-3611

[113] Stambolic V et al. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell, 1998, 95: 29-39

[114] Liu X et al. Lifelong accumulation of bone in mice lacking Pten in osteoblasts. Proc. Natl Acad. Sci. USA., 2007, 104: 2259-2264

[115] Guntur AR, Reinhold MI, Cuellar J Jr., Naski MC. Conditional ablation of Pten in osteoprogenitors stimulates FGF signaling. Development, 2011, 138: 1433-1444

[116] Ford-Hutchinson AF et al. Inactivation of Pten in osteo-chondroprogenitor cells leads to epiphyseal growth plate abnormalities and skeletal overgrowth. J. Bone Miner. Res., 2007, 22: 1245-1259

[117] Burgers TA et al. Mice lacking pten in osteoblasts have improved intramembranous and late endochondral fracture healing. PLoS One, 2013, 8: e63857

[118] Collins CJ et al. Fracture healing in mice lacking Pten in osteoblasts: a micro-computed tomography image-based analysis of the mechanical properties of the femur. J. Biomech., 2015, 48: 310-317

[119] Liu X, Chen T, Wu Y, Tang Z. Role and mechanism of PTEN in adiponectin-induced osteogenesis in human bone marrow mesenchymal stem cells. Biochem. Biophys. Res. Commun., 2017, 483: 712-717

[120] Ge JB et al. MiR-374b promotes osteogenic differentiation of MSCs by degrading PTEN and promoting fracture healing. Eur. Rev. Med. Pharmacol. Sci., 2018, 22: 3303-3310

[121] Yang L et al. The long non-coding RNA-ORLNC1 regulates bone mass by directing mesenchymal stem cell fate. Mol. Ther., 2019, 27: 394-410

[122] Yang T, Moore M, He F. Pten regulates neural crest proliferation and differentiation during mouse craniofacial development. Dev. Dyn., 2018, 247: 304-314

[123] Ye L et al. NUMB maintains bone mass by promoting degradation of PTEN and GLI1 via ubiquitination in osteoblasts. Bone Res., 2018, 6: 32

[124] Caselli A et al. Low molecular weight protein tyrosine phosphatase: Multifaceted functions of an evolutionarily conserved enzyme. Biochim. Biophys. Acta, 2016, 1864: 1339-1355

[125] Bucciantini M et al. The low Mr phosphotyrosine protein phosphatase behaves differently when phosphorylated at Tyr131 or Tyr132 by Src kinase. FEBS Lett., 1999, 456: 73-78

[126] Rigacci S et al. pp60v-src phosphorylates and activates low molecular weight phosphotyrosine-protein phosphatase. J. Biol. Chem., 1996, 271: 1278-1281

[127] Zambuzzi WF et al. Modulation of Src activity by low molecular weight protein tyrosine phosphatase during osteoblast differentiation. Cell Physiol. Biochem., 2008, 22: 497-506

[128] de Souza Malaspina TS et al. A possible mechanism of low molecular weight protein tyrosine phosphatase (LMW-PTP) activity modulation by glutathione action during human osteoblast differentiation. Arch. Oral. Biol., 2009, 54: 642-650

[129] Fernandes GV et al. Osteoblast adhesion dynamics: a possible role for ROS and LMW-PTP. J. Cell Biochem., 2014, 115: 1063-1069

[130] Milani R et al. Phosphoproteome reveals an atlas of protein signaling networks during osteoblast adhesion. J. Cell Biochem., 2010, 109: 957-966

[131] Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature, 2003, 423: 337-342

[132] Mun SH, Park PSU, Park-Min KH. The M-CSF receptor in osteoclasts and beyond. Exp. Mol. Med., 2020, 52: 1239-1254

[133] Tonks NK, Charbonneau H, Diltz CD, Fischer EH, Walsh KA. Demonstration that the leukocyte common antigen CD45 is a protein tyrosine phosphatase. Biochemistry, 1988, 27: 8695-8701

[134] Shivtiel S et al. CD45 regulates retention, motility, and numbers of hematopoietic progenitors, and affects osteoclast remodeling of metaphyseal trabecules. J. Exp. Med., 2008, 205: 2381-2395

[135] Schmidt A et al. Protein-tyrosine phosphatase activity regulates osteoclast formation and function: inhibition by alendronate. Proc. Natl. Acad. Sci. USA, 1996, 93: 3068-3073

[136] Peretz A et al. Hypomyelination and increased activity of voltage-gated K(+) channels in mice lacking protein tyrosine phosphatase epsilon. EMBO J., 2000, 19: 4036-4045

[137] Chiusaroli R et al. Tyrosine phosphatase epsilon is a positive regulator of osteoclast function in vitro and in vivo. Mol. Biol. Cell, 2004, 15: 234-244

[138] Granot-Attas S, Elson A. Protein tyrosine phosphatases in osteoclast differentiation, adhesion, and bone resorption. Eur. J. Cell Biol., 2008, 87: 479-490

[139] Granot-Attas S, Luxenburg C, Finkelshtein E, Elson A. Protein tyrosine phosphatase epsilon regulates integrin-mediated podosome stability in osteoclasts by activating Src. Mol. Biol. Cell, 2009, 20: 4324-4334

[140] Ku B et al. Identification of N-(5-(phenoxymethyl)-1,3,4-thiadiazol-2-yl)acetamide derivatives as novel protein tyrosine phosphatase epsilon inhibitors exhibiting anti-osteoclastic activity. Bioorg. Med. Chem., 2018, 26: 5204-5211

[141] Pixley FJ, Lee PS, Dominguez MG, Einstein DB, Stanley ER. A heteromorphic protein-tyrosine phosphatase, PTP phi, is regulated by CSF-1 in macrophages. J. Biol. Chem., 1995, 270: 27339-27347

[142] Yang JH, Amoui M, Lau KH. Targeted deletion of the osteoclast protein-tyrosine phosphatase (PTP-oc) promoter prevents RANKL-mediated osteoclastic differentiation of RAW264.7 cells. FEBS Lett., 2007, 581: 2503-2508

[143] Sheng MH et al. Targeted transgenic expression of an osteoclastic transmembrane protein-tyrosine phosphatase in cells of osteoclastic lineage increases bone resorption and bone loss in male young adult mice. J. Biol. Chem., 2009, 284: 11531-11545

[144] Suhr SM, Pamula S, Baylink DJ, Lau KH. Antisense oligodeoxynucleotide evidence that a unique osteoclastic protein-tyrosine phosphatase is essential for osteoclastic resorption. J. Bone Miner. Res., 2001, 16: 1795-1803

[145] Amoui M, Suhr SM, Baylink DJ, Lau KH. An osteoclastic protein-tyrosine phosphatase may play a role in differentiation and activity of human monocytic U-937 cell-derived, osteoclast-like cells. Am. J. Physiol. Cell Physiol., 2004, 287: C874-C884

[146] Amoui M, Sheng MH, Chen ST, Baylink DJ, Lau KH. A transmembrane osteoclastic protein-tyrosine phosphatase regulates osteoclast activity in part by promoting osteoclast survival through c-Src-dependent activation of NFkappaB and JNK2. Arch. Biochem. Biophys., 2007, 463: 47-59

[147] Roth L et al. Phosphorylation of the phosphatase PTPROt at Tyr(399) is a molecular switch that controls osteoclast activity and bone mass in vivo. Sci. Signal, 2019, 12: eaau0240

[148] Lau KH, Stiffel V, Amoui M. An osteoclastic protein-tyrosine phosphatase regulates the beta3-integrin, syk, and shp1 signaling through respective src-dependent phosphorylation in osteoclasts. Am. J. Physiol. Cell Physiol., 2012, 302: C1676-C1686

[149] Lau KH, Amoui M, Stiffel V, Chen ST, Sheng MH. An osteoclastic transmembrane protein-tyrosine phosphatase enhances osteoclast activity in part by dephosphorylating EphA4 in osteoclasts. J. Cell Biochem., 2015, 116: 1785-1796

[150] Lau KW et al. Conditional disruption of miR17~92 in osteoclasts led to activation of osteoclasts and loss of trabecular bone in part through suppression of the miR17-mediated downregulation of protein-tyrosine phosphatase-oc in mice. J. Bone Miner. Res., 2017, 1: 73-85

[151] Yasuda H et al. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc. Natl. Acad. Sci. USA, 1998, 95: 3597-3602

[152] Udagawa N et al. Osteoprotegerin produced by osteoblasts is an important regulator in osteoclast development and function. Endocrinology, 2000, 141: 3478-3484

[153] Zee T, Settembre C, Levine RL, Karsenty G. T-cell protein tyrosine phosphatase regulates bone resorption and whole-body insulin sensitivity through its expression in osteoblasts. Mol. Cell Biol., 2012, 32: 1080-1088

[154] Doody KM et al. T cell protein tyrosine phosphatase deficiency results in spontaneous synovitis and subchondral bone resorption in mice. Arthritis Rheum., 2012, 64: 752-761

[155] Zhang Z, Jimi E, Bothwell ALM. Receptor activator of NF-κB ligand stimulates recruitment of SHP-1 to the complex containing TNFR-associated factor 6 that regulates osteoclastogenesis. J. Immunol., 2003, 171: 3620-3626

[156] Mori Y et al. Inhibitory immunoglobulin-like receptors LILRB and PIR-B negatively regulate osteoclast development. J. Immunol., 2008, 181: 4742-4751

[157] Wu Y, Tworkoski K, Michaud M, Madri JA. Bone marrow monocyte PECAM-1 deficiency elicits increased osteoclastogenesis resulting in trabecular bone loss. J. Immunol., 2009, 182: 2672-2679

[158] Csete D et al. Hematopoietic or osteoclast-specific deletion of Syk leads to increased bone mass in experimental mice. Front. Immunol., 2019, 10: 937

[159] Mocsai A et al. The immunomodulatory adapter proteins DAP12 and Fc receptor gamma-chain (FcRgamma) regulate development of functional osteoclasts through the Syk tyrosine kinase. Proc. Natl. Acad. Sci. USA, 2004, 101: 6158-6163

[160] Huang ZY, Hunter S, Kim MK, Indik ZK, Schreiber AD. The effect of phosphatases SHP-1 and SHIP-1 on signaling by the ITIM- and ITAM-containing Fcgamma receptors FcgammaRIIB and FcgammaRIIA. J. Leukoc. Biol., 2003, 73: 823-829

[161] Peng Q et al. TREM2- and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1. Sci. Signal., 2010, 3: ra38

[162] Hayashi M et al. Ly49Q, an ITIM-bearing NK receptor, positively regulates osteoclast differentiation. Biochem. Biophys. Res. Commun., 2010, 393: 432-438

[163] Chiu YH, Ritchlin CT. DC-STAMP: a key regulator in osteoclast differentiation. J. Cell Physiol., 2016, 231: 2402-2407

[164] Chiu YH et al. Regulation of human osteoclast development by dendritic cell-specific transmembrane protein (DC-STAMP). J. Bone Miner. Res., 2012, 27: 79-92

[165] Deschaseaux F et al. Regulation and function of immunosuppressive molecule human leukocyte antigen G5 in human bone tissue. FASEB J., 2013, 27: 2977-2987

[166] Ke K et al. Reactive oxygen species induce the association of SHP-1 with c-Src and the oxidation of both to enhance osteoclast survival. Am. J. Physiol. Endocrinol. Metab., 2014, 307: E61-E70

[167] Maile LA et al. An essential role for the association of CD47 to SHPS-1 in skeletal remodeling. J. Bone Miner. Res., 2011, 26: 2068-2081

[168] van Beek EM et al. Inhibitory regulation of osteoclast bone resorption by signal regulatory protein alpha. FASEB J., 2009, 23: 4081-4090

[169] Sick E et al. CD47 update: a multifaceted actor in the tumour microenvironment of potential therapeutic interest. Br. J. Pharmacol., 2012, 167: 1415-1430

[170] Koskinen C et al. Lack of CD47 impairs bone cell differentiation and results in an osteopenic phenotype in vivo due to impaired signal regulatory protein alpha (SIRPalpha) signaling. J. Biol. Chem., 2013, 288: 29333-29344

[171] Pao LI et al. B cell-specific deletion of protein-tyrosine phosphatase Shp1 promotes B-1a cell development and causes systemic autoimmunity. Immunity, 2007, 27: 35-48

[172] Abram CL, Lowell CA. Shp1 function in myeloid cells. J. Leukoc. Biol., 2017, 102: 657-675

[173] Lee AW SD. Both src-dependent and -independent mechanisms mediate phosphatidylinositol 3-kinase regulation of colony-stimulating factor 1-activated mitogen-activated protein kinases in myeloid progenitors. Mol. Cell Biol., 2000, 20: 6770-6798

[174] Liu Y, Jenkins B, Shin JL, Rohrschneider LR. Scaffolding protein Gab2 mediates differentiation signaling downstream of Fms receptor tyrosine kinase. Mol. Cell Biol., 2001, 21: 3047-3056

[175] Bauler TJ et al. Development of severe skeletal defects in induced SHP-2-deficient adult mice: a model of skeletal malformation in humans with SHP-2 mutations. Dis. Models Mechanisms, 2011, 4: 228-239

[176] Chan G et al. Essential role for Ptpn11 in survival of hematopoietic stem and progenitor cells. Blood, 2011, 117: 4253-4261

[177] Wang L et al. A ERK/RSK-mediated negative feedback loop regulates M-CSF-evoked PI3K/AKT activation in macrophages. FASEB J., 2017, 32: 875-887

[178] Zhou Y et al. SHP2 regulates osteoclastogenesis by promoting preosteoclast fusion. FASEB J., 2015, 29: 1635-1645

[179] Yin H et al. Inhibition of Src homology 2 domain-containing protein tyrosine phosphatase-2 facilitates CD31hiEndomucinhi blood vessel and bone formation in ovariectomized mice. Cell Physiol. Biochem., 2018, 50: 1068-1083

[180] Tamura T et al. Soluble interleukin-6 receptor triggers osteoclast formation by interleukin 6. Proc. Natl. Acad. Sci. USA, 1993, 90: 11924-11928

[181] Romas E et al. The role of gp130-mediated signals in osteoclast development: regulation of interleukin 11 production by osteoblasts and distribution of its receptor in bone marrow cultures. J. Exp. Med., 1996, 183: 2581-2591

[182] Sims NA et al. Glycoprotein 130 regulates bone turnover and bone size by distinct downstream signaling pathways. J. Clin. Investig., 2004, 113: 379-389

[183] Chia LY, Walsh NC, Martin TJ, Sims NA. Isolation and gene expression of haematopoietic-cell-free preparations of highly purified murine osteocytes. Bone, 2015, 72: 34-42

[184] Soriano P, Montgomery C, Geske R, Bradley A. Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell, 1991, 64: 693-702

[185] Lowe C et al. Osteopetrosis in Src-deficient mice is due to an autonomous defect of osteoclasts. Proc. Natl. Acad. Sci. USA, 1993, 90: 4485-4489

[186] Kim JH, Kim K, Kim I, Seong S, Kim N. c-Src-dependent and -independent functions of matk in osteoclasts and osteoblasts. J. Immunol., 2018, 200: 2455-2463

[187] Rhee I, Davidson D, Souza CM, Vacher J, Veillette A. Macrophage fusion is controlled by the cytoplasmic protein tyrosine phosphatase PTP-PEST/PTPN12. Mol. Cell Biol., 2013, 33: 2458-2469

[188] Gupta A et al. Leupaxin is a critical adaptor protein in the adhesion zone of the osteoclast. J. Bone Miner. Res., 2003, 18: 669-685

[189] Chellaiah MA, Kuppuswamy D, Lasky L, Linder S. Phosphorylation of a Wiscott-Aldrich syndrome protein-associated signal complex is critical in osteoclast bone resorption. J. Biol. Chem., 2007, 282: 10104-10116

[190] 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. J. Biol. Chem., 2001, 276: 47434-47444

[191] Chellaiah MA, Schaller MD. Activation of Src kinase by protein-tyrosine phosphatase-PEST in osteoclasts: comparative analysis of the effects of bisphosphonate and protein-tyrosine phosphatase inhibitor on Src activation in vitro. J. Cell Physiol., 2009, 220: 382-393

[192] Eleniste PP, Du L, Shivanna M, Bruzzaniti A. Dynamin and PTP-PEST cooperatively regulate Pyk2 dephosphorylation in osteoclasts. Int. J. Biochem. Cell Biol., 2012, 44: 790-800

[193] Valerio MS et al. MKP-1 signaling events are required for early osteoclastogenesis in lineage defined progenitor populations by disrupting RANKL-induced NFATc1 nuclear translocation. Bone, 2014, 60: 16-25

[194] Griffin AC 3rd, Kern MJ, Kirkwood KL. MKP-1 is essential for canonical vitamin D-induced signaling through nuclear import and regulates RANKL expression and function. Mol. Endocrinol., 2012, 26: 1682-1693

[195] Sartori R, Li F, Kirkwood KL. MAP kinase phosphatase-1 protects against inflammatory bone loss. J. Dent. Res., 2009, 88: 1125-1130

[196] Carlson J et al. Role of MKP-1 in osteoclasts and bone homeostasis. Am. J. Pathol., 2009, 175: 1564-1573

[197] Vattakuzhi Y, Abraham SM, Freidin A, Clark AR, Horwood NJ. Dual-specificity phosphatase 1-null mice exhibit spontaneous osteolytic disease and enhanced inflammatory osteolysis in experimental arthritis. Arthritis Rheumatol., 2012, 64: 2201-2210

[198] Yu H et al. Anti-inflammatory effect of MAPK phosphatase-1 local gene transfer in inflammatory bone loss. Gene. Ther., 2011, 18: 344-353

[199] Choi Y, Yoo JH, Lee Y, Bae MK, Kim HJ. Calcium-phosphate crystals promote RANKL expression via the downregulation of DUSP1. Mol. Cells, 2019, 42: 183-188

[200] Moon SJ et al. Dual-specificity phosphatase 5 attenuates autoimmune arthritis in mice via reciprocal regulation of the Th17/Treg cell balance and inhibition of osteoclastogenesis. Arthritis Rheumatol., 2014, 66: 3083-3095

[201] Modinger Y et al. C5aR1 interacts with TLR2 in osteoblasts and stimulates the osteoclast-inducing chemokine CXCL10. J. Cell Mol. Med., 2018, 22: 6002-6014

[202] Soysa NS, Alles N. Positive and negative regulators of osteoclast apoptosis. Bone Rep., 2019, 11: 100225

[203] McDonald MM et al. Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption. Cell, 2021, 184: 1330-1347 e1313

[204] Bluml S et al. Loss of phosphatase and tensin homolog (PTEN) in myeloid cells controls inflammatory bone destruction by regulating the osteoclastogenic potential of myeloid cells. Ann. Rheum. Dis., 2015, 74: 227-233

[205] Sugatani T, Alvarez U, Hruska KA. PTEN regulates RANKL- and osteopontin-stimulated signal transduction during osteoclast differentiation and cell motility. J. Biol. Chem., 2003, 278: 5001-5008

[206] Jang HD, Noh JY, Shin JH, Lin JJ, Lee SY. PTEN regulation by the Akt/GSK-3beta axis during RANKL signaling. Bone, 2013, 55: 126-131

[207] Zhao C et al. miR-214 promotes osteoclastogenesis by targeting Pten/PI3k/Akt pathway. RNA Biol., 2015, 12: 343-353

[208] Lou Z et al. miR-142-5p promotes the osteoclast differentiation of bone marrow-derived macrophages via PTEN/PI3K/AKT/FoxO1 pathway. J. Bone Miner. Metab., 2019, 37: 815-824

[209] Tu KN et al. Osteoporosis: a review of treatment options. P T., 2018, 43: 92-104

[210] DeLise AM, Fischer L, Tuan RS. Cellular interactions and signaling in cartilage development. Osteoarthr. Cartil., 2000, 8: 309-334

[211] Kaspiris A et al. Expression of the growth factor pleiotrophin and its receptor protein tyrosine phosphatase beta/zeta in the serum, cartilage and subchondral bone of patients with osteoarthritis. Jt. Bone Spine, 2013, 80: 407-413

[212] Pufe T, Groth G, Goldring MB, Tillmann B, Mentlein R. Effects of pleiotrophin, a heparin-binding growth factor, on human primary and immortalized chondrocytes. Osteoarthr. Cartil., 2007, 15: 155-162

[213] Kaspiris A et al. Effects of mechanical loading on the expression of pleiotrophin and its receptor protein tyrosine phosphatase beta/zeta in a rat spinal deformity model. Cytokine, 2016, 78: 7-15

[214] Augustine KA et al. Evidence that the protein tyrosine phosphatase (PC12,Br7,Sl) gamma (-) isoform modulates chondrogenic patterning and growth. Int. J. Dev. Biol., 2000, 44: 361-371

[215] Gagarina V et al. SirT1 enhances survival of human osteoarthritic chondrocytes by repressing protein tyrosine phosphatase 1B and activating the insulin-like growth factor receptor pathway. Arthritis Rheum., 2010, 62: 1383-1392

[216] Yamamoto H, Schoonjans K, Auwerx J. Sirtuin functions in health and disease. Mol. Endocrinol., 2007, 21: 1745-1755

[217] Gabay O et al. Sirt1-deficient mice exhibit an altered cartilage phenotype. Jt. Bone Spine, 2013, 80: 613-620

[218] Kim HK, Feng GS, Chen D, King PD, Kamiya N. Targeted disruption of Shp2 in chondrocytes leads to metachondromatosis with multiple cartilaginous protrusions. J. Bone Miner. Res., 2013, 29: 761-769

[219] Bowen ME AU, Kurek KC, Yang W, Warman ML. SHP2 Regulates Chondrocyte Terminal Differentiation, Growth Plate Architecture and Skeletal Cell Fates. PLoS Genet., 2014, 10: e1004364

[220] Tajan M et al. Noonan syndrome-causing SHP2 mutants impair ERK-dependent chondrocyte differentiation during endochondral bone growth. Hum. Mol. Genet., 2018, 27: 2276-2289

[221] Krejci P et al. Bisindolylmaleimide I suppresses fibroblast growth factor-mediated activation of Erk MAP kinase in chondrocytes by preventing Shp2 association with the Frs2 and Gab1 adaptor proteins. J. Biol. Chem., 2007, 282: 2929-2936

[222] Koshimizu T et al. Vinculin functions as regulator of chondrogenesis. J. Biol. Chem., 2012, 287: 15760-15775

[223] Guan Y, Yang X, Yang W, Charbonneau C, Chen Q. Mechanical activation of mammalian target of rapamycin pathway is required for cartilage development. FASEB J., 2014, 28: 4470-4481

[224] Kamiya N et al. SHP2-deficiency in chondrocytes deforms orofacial cartilage and ciliogenesis in mice. J. Bone Miner. Res., 2015, 30: 2028-2032

[225] Hashizume M, Mihara M. High molecular weight hyaluronic acid inhibits IL-6-induced MMP production from human chondrocytes by up-regulating the ERK inhibitor, MKP-1. Biochem. Biophys. Res. Commun., 2010, 403: 184-189

[226] Nieminen R, Korhonen R, Moilanen T, Clark AR, Moilanen E. Aurothiomalate inhibits cyclooxygenase 2, matrix metalloproteinase 3, and interleukin-6 expression in chondrocytes by increasing MAPK phosphatase 1 expression and decreasing p38 phosphorylation: MAPK phosphatase 1 as a novel target for antirheumatic drugs. Arthritis Rheum., 2010, 62: 1650-1659

[227] Li TF et al. Aberrant hypertrophy in Smad3-deficient murine chondrocytes is rescued by restoring transforming growth factor beta-activated kinase 1/activating transcription factor 2 signaling: a potential clinical implication for osteoarthritis. Arthritis Rheum., 2010, 62: 2359-2369

[228] Carpio LR, Bradley EW, Westendorf JJ. Histone deacetylase 3 suppresses Erk phosphorylation and matrix metalloproteinase (Mmp)-13 activity in chondrocytes. Connect Tissue Res., 2017, 58: 27-36

[229] Furuta J et al. High molecular weight hyaluronic acid regulates MMP13 expression in chondrocytes via DUSP10/MKP5. J. Orthop. Res., 2017, 35: 331-339

[230] Snelling S et al. A gene expression study of normal and damaged cartilage in anteromedial gonarthrosis, a phenotype of osteoarthritis. Osteoarthr. Cartil., 2014, 22: 334-343

[231] Patterson KI, Brummer T, O’Brien PM, Daly RJ. Dual-specificity phosphatases: critical regulators with diverse cellular targets. Biochem. J., 2009, 418: 475-489

[232] Wang Y, Xu Z, Wang J, Xu S. DUSP19, a downstream effector of leptin, inhibits chondrocyte apoptosis via dephosphorylating JNK during osteoarthritis pathogenesis. Mol. Biosyst., 2016, 12: 721-728

[233] Yao ZZ, Hu AX, Liu XS. DUSP19 regulates IL-1beta-induced apoptosis and MMPs expression in rat chondrocytes through JAK2/STAT3 signaling pathway. Biomed. Pharmacother., 2017, 96: 1209-1215

[234] Yang G et al. PTEN deficiency causes dyschondroplasia in mice by enhanced hypoxia-inducible factor 1alpha signaling and endoplasmic reticulum stress. Development, 2008, 135: 3587-3597

[235] Hsieh SC, Chen NT, Lo SH. Conditional loss of PTEN leads to skeletal abnormalities and lipoma formation. Mol. Carcinog., 2009, 48: 545-552

[236] Iwasa K et al. PTEN regulates matrix synthesis in adult human chondrocytes under oxidative stress. J. Orthop. Res., 2014, 32: 231-237

[237] Zhang Y et al. MicroRNA-130a regulates chondrocyte proliferation and alleviates osteoarthritis through PTEN/PI3K/Akt signaling pathway. Int. J. Mol. Med., 2018, 41: 3699-3708

[238] Huang Z, Zhang N, Ma W, Dai X, Liu J. MiR-337-3p promotes chondrocytes proliferation and inhibits apoptosis by regulating PTEN/AKT axis in osteoarthritis. Biomed. Pharmacother., 2017, 95: 1194-1200

[239] Cheng X et al. Mesenchymal stem cells deliver exogenous miR-21 via exosomes to inhibit nucleus pulposus cell apoptosis and reduce intervertebral disc degeneration. J. Cell Mol. Med., 2018, 22: 261-276

[240] Wang B, Wang D, Yan T, Yuan H. MiR-138-5p promotes TNF-alpha-induced apoptosis in human intervertebral disc degeneration by targeting SIRT1 through PTEN/PI3K/Akt signaling. Exp. Cell Res., 2016, 345: 199-205

[241] Wang WJ et al. MiR-21 promotes ECM degradation through inhibiting autophagy via the PTEN/akt/mTOR signaling pathway in human degenerated NP cells. Biomed. Pharmacother., 2018, 99: 725-734

[242] Wu XF, Zhou ZH, Zou J. MicroRNA-181 inhibits proliferation and promotes apoptosis of chondrocytes in osteoarthritis by targeting PTEN. Biochem. Cell Biol., 2017, 95: 437-444

[243] Rundle CH, Kappen C. Developmental expression of the murine Prl-1 protein tyrosine phosphatase gene. J. Exp. Zool., 1999, 283: 612-617

[244] Cohen MM Jr., Gorlin RJ. Noonan-like/multiple giant cell lesion syndrome. Am. J. Med. Genet., 1991, 40: 159-166

[245] Bufalino A, Carrera M, Carlos R, Coletta RD. Giant cell lesions in noonan syndrome: case report and review of the literature. Head. Neck Pathol., 2010, 4: 174-177

[246] Keren B et al. PTPN11 mutations in patients with LEOPARD syndrome: a French multicentric experience. J. Med. Genet., 2004, 41: e117

[247] Tartaglia M et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat. Genet., 2001, 29: 465-468

[248] Porciello R et al. Leopard syndrome. Dermatol Online J., 2008, 14: 7

[249] Sarkozy A, Digilio MC, Dallapiccola B. Leopard syndrome. Orphanet. J. Rare Dis., 2008, 3

[250] Venugopal V, Romero CJ. Endocrine complications of Noonan syndrome beyond short stature. Pediatr. Endocrinol. Rev., 2019, 16: 465-470

[251] Rickard S et al. Oto-facio-cervical (OFC) syndrome is a contiguous gene deletion syndrome involving EYA1: molecular analysis confirms allelism with BOR syndrome and further narrows the Duane syndrome critical region to 1 cM. Hum. Genet., 2001, 108: 398-403

[252] Ohba S, He X, Hojo H, McMahon AP. Distinct transcriptional programs underlie Sox9 regulation of the mammalian chondrocyte. Cell Rep., 2015, 12: 229-243

[253] Zhang H et al. An Eya1-Notch axis specifies bipotential epibranchial differentiation in mammalian craniofacial morphogenesis. Elife, 2017, 6: e30126

[254] Jiang Y et al. Germline PTPRD mutations in Ewing sarcoma: biologic and clinical implications. Oncotarget, 2013, 4: 884-889

[255] Subbiah V et al. Personalized comprehensive molecular profiling of high risk osteosarcoma: Implications and limitations for precision medicine. Oncotarget, 2015, 6: 40642-40654

[256] Jiang Y et al. Novel secondary somatic mutations in Ewing’s sarcoma and desmoplastic small round cell tumors. PLoS One, 2014, 9: e93676

[257] Abaan OD et al. PTPL1 is a direct transcriptional target of EWS-FLI1 and modulates Ewing’s Sarcoma tumorigenesis. Oncogene, 2005, 24: 2715-2722

[258] Toledo SR et al. Bone deposition, bone resorption, and osteosarcoma. J. Orthop. Res., 2010, 28: 1142-1148

[259] Xi Y, Chen Y. PTEN plays dual roles as a tumor suppressor in osteosarcoma cells. J. Cell Biochem., 2017, 118: 2684-2692

[260] Bowen ME et al. Loss-of-function mutations in PTPN11 cause metachondromatosis, but not Ollier disease or Maffucci syndrome. PLoS Genet., 2011, 7: e1002050

[261] Sobreira NL et al. Whole-genome sequencing of a single proband together with linkage analysis identifies a Mendelian disease gene. PLoS Genet., 2010, 6: e1000991

[262] Debnath S et al. Discovery of a periosteal stem cell mediating intramembranous bone formation. Nature, 2018, 562: 133-139

[263] Feng H et al. Tendon-derived cathepsin K-expressing progenitor cells activate Hedgehog signaling to drive heterotopic ossification. J. Clin. Investig., 2020, 130: 6354-6365

[264] Yang W, Neel BG. From an orphan disease to a generalized molecular mechanism: PTPN11 loss-of-function mutations in the pathogenesis of metachondromatosis. Rare Dis., 2013, 1: e26657

[265] Miah SMS JC et al. Ptpn11 deletion in cD4+ cells does not affect T cell development and functions but causes cartilage tumors in a T cell-independent manner. Front. Immunol., 2017, 8: 1326

[266] Guittard G et al. Unexpected cartilage phenotype in CD4-Cre-conditional SOS-deficient mice. Front. Immunol., 2017, 8: 343

[267] Shiokawa M et al. Spontaneous chondroma formation in CD2-Cre-driven Erk-deficient mice. Int. Immunol., 2017, 29: 479-485

[268] Chen YN et al. Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases. Nature, 2016, 535: 148-152

[269] Lantz KA et al. Inhibition of PTP1B by trodusquemine (MSI-1436) causes fat-specific weight loss in diet-induced obese mice. Obesity, 2010, 18: 1516-1523

[270] Krishnan N et al. Targeting the disordered C terminus of PTP1B with an allosteric inhibitor. Nat. Chem. Biol., 2014, 10: 558-566

[271] Watt GF, Scott-Stevens P, Gaohua L. Targeted protein degradation in vivo with proteolysis targeting chimeras: current status and future considerations. Drug Discov. Today Technol., 2019, 31: 69-80

[272] Wang M, Lu J, Wang M, Yang CY, Wang S. Discovery of SHP2-D26 as a first, potent, and effective PROTAC degrader of SHP2 protein. J. Med. Chem., 2020, 63: 7510-7528

[273] Tonks NK, Diltz CD, Fischer EH. Characterization of the major protein-tyrosine-phosphatases of human placenta. J. Biol. Chem., 1988, 263: 6731-6737

Funding

U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)(RO1AR066746)

U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)(1P20 GM119943)