Bone Metabolism Alterations in Systemic Sclerosis: An Insight into Bone
Disease in SSc: From the Radiographic Findings to their Potential
Pathogenesis and Outcome

Stefania      Sciacca; Addolorata      Corrado; Cinzia      Rotondo; Francesco   Paolo   Cantatore
Abstract

Previous research has shown conflicting reports about the effect of systemic sclerosis (SSc) on bone metabolism, especially considering bone mineral density (BMD), bone microarchitecture, and risk of fracture. The objective of this review is to analyze data from previous articles to investigate the differences in BMD and fracture risk between SSc and non-SSc populations and to discuss potential underlying mechanisms. The main factors investigated have been BMD (mean and standard deviation), t-scores and z-scores at the lumbar spine, femoral neck, and total hip measured by dual-energy X-ray absorptiometry (DEXA), bone remodeling markers, fracture prevalence, and incidence, trabecular bone score (TBS), musculoskeletal involvement with particular correlation to SSc skin subtype and extent, disease duration, serological pattern, and vitamin D levels. Since microvascular alterations evaluated through nailfold videocapillaroscopy (NVC) of SSc patients have recently been correlated with decreased BMD and bone microarchitecture, the vascular impairment in SSc has been proposed as a remarkable contributing element in bone remodeling, and the role of hypoxia has been investigated.
Keywords: Systemic sclerosis, calcinosis, bone mineral density, risk fracture, acroosteolysis, osteoporosis, bone turnover markers, vitamin D.
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Graphical Abstract

[1]
Pattanaik D, Brown M, Postlethwaite BC, Postlethwaite AE. Pathogenesis of systemic sclerosis. Front Immunol  2015; 6: 272.
 [http://dx.doi.org/10.3389/fimmu.2015.00272] [PMID: 26106387]

[2]
Consensus development conference: Diagnosis, prophylaxis, and treatment of osteoporosis. Am J Med  1993; 94(6): 646-50.
 [http://dx.doi.org/10.1016/0002-9343(93)90218-E] [PMID: 8506892]

[3]
Pagkopoulou E, Arvanitaki A, Daoussis D, Garyfallos A, Kitas G, Dimitroulas T. Comorbidity burden in systemic sclerosis: Beyond disease-specific complications. Rheumatol Int  2019; 39(9): 1507-17.
 [http://dx.doi.org/10.1007/s00296-019-04371-z] [PMID: 31300848]

[4]
Omair MA, Pagnoux C, McDonald-Blumer H, Johnson SR. Low bone density in systemic sclerosis. A systematic review. J Rheumatol  2013; 40(11): 1881-90.
 [http://dx.doi.org/10.3899/jrheum.130032] [PMID: 24037552]

[5]
Rios Fernández R, Fernández Roldán C, Callejas Rubio JL, Ortego Centeno N, Vitamin D. Vitamin D deficiency in a cohort of patients with systemic scleroderma from the south of Spain. J Rheumatol  2010; 37(6): 1355-5.
 [http://dx.doi.org/10.3899/jrheum.091143] [PMID: 20516041]

[6]
Frediani B, Baldi F, Falsetti P, et al. Clinical determinants of bone mass and bone ultrasonometry in patients with systemic sclerosis. Clin Exp Rheumatol  2004; 22(3): 313-8.
 [PMID: 15144125]

[7]
Di Munno O, Mazzantini M, Massei P, et al. Reduced bone mass and normal calcium metabolism in systemic sclerosis with and without calcinosis. Clin Rheumatol  1995; 14(4): 407-12.
 [http://dx.doi.org/10.1007/BF02207673] [PMID: 7586976]

[8]
Dovio A, Data V, Carignola R, et al. Circulating osteoprotegerin and soluble RANK ligand in systemic sclerosis. J Rheumatol  2008; 35(11): 2206-13.
 [http://dx.doi.org/10.3899/jrheum.080192] [PMID: 18843778]

[9]
Sampaio-Barros PD, Costa-Paiva L, Filardi S, Sachetto Z, Samara AM, Marques-Neto JF. Prognostic factors of low bone mineral density in systemic sclerosis. Clin Exp Rheumatol  2005; 23(2): 180-4.
 [PMID: 15895887]

[10]
Thietart S, Louati K, Gatfosse M, et al. Overview of osteo-articular involvement in systemic sclerosis: Specific risk factors, clinico-sonographic evaluation, and comparison with healthy women from the French OFELY cohort. Best Pract Res Clin Rheumatol  2018; 32(4): 591-604.
 [http://dx.doi.org/10.1016/j.berh.2019.01.008] [PMID: 31174827]

[11]
Alexandersson BT, Geirsson AJ, Olafsson I, Franzson L, Sigurdsson G, Gudbjornsson B. Bone mineral density and bone turnover in systemic sclerosis. Laeknabladid  2007; 93(7-8): 535-41.
 [PMID: 17823496]

[12]
Souza RB, Borges CT, Takayama L, Aldrighi JM, Pereira RM. Systemic sclerosis and bone loss: The role of the disease and body composition. Scand J Rheumatol  2006; 35(5): 384-7.
 [http://dx.doi.org/10.1080/03009740600704296] [PMID: 17062439]

[13]
Chen J, Lei L, Pan J, Zhao C. A meta-analysis of fracture risk and bone mineral density in patients with systemic sclerosis. Clin Rheumatol  2020; 39(4): 1181-9.
 [http://dx.doi.org/10.1007/s10067-019-04847-0] [PMID: 31838641]

[14]
Ruaro B, Casabella A, Paolino S, et al. Correlation between bone quality and microvascular damage in systemic sclerosis patients. Rheumatology (Oxford)  2018; 57(9): 1548-54.
 [http://dx.doi.org/10.1093/rheumatology/key130] [PMID: 29788459]

[15]
Kilic G, Kilic E, Akgul O, Ozgocmen S. Increased risk for bone loss in women with systemic sclerosis: A comparative study with rheumatoid arthritis. Int J Rheum Dis  2016; 19(4): 405-11.
 [http://dx.doi.org/10.1111/1756-185X.12242] [PMID: 24283757]

[16]
Yuen SY, Rochwerg B, Ouimet J, Pope JE. Patients with scleroderma may have increased risk of osteoporosis. A comparison to rheumatoid arthritis and noninflammatory musculoskeletal conditions. J Rheumatol  2008; 35(6): 1073-8.
 [PMID: 18412305]

[17]
Avouac J, Koumakis E, Toth E, et al. Increased risk of osteoporosis and fracture in women with systemic sclerosis: A comparative study with rheumatoid arthritis. Arthritis Care Res (Hoboken)  2012; 64(12): 1871-8.
 [http://dx.doi.org/10.1002/acr.21761] [PMID: 22730393]

[18]
Taylan A, Birlik M, Kenar G, et al. Osteoprotegrin interacts with biomarkers and cytokines that have roles in osteoporosis, skin fibrosis, and vasculopathy in systemic sclerosis: A potential multifaceted relationship between OPG/RANKL/TRAIL and Wnt inhibitors. Mod Rheumatol  2019; 29(4): 619-24.
 [http://dx.doi.org/10.1080/14397595.2018.1500736] [PMID: 30001654]

[19]
Corrado A, Colia R, Mele A, et al. Relationship between body mass composition, bone mineral density, skin fibrosis and 25(OH) vitamin D serum levels in systemic sclerosis. PLoS One  2015; 10(9): e0137912.
 [http://dx.doi.org/10.1371/journal.pone.0137912] [PMID: 26375284]

[20]
Marighela TF, Genaro PS, Pinheiro MM, Szejnfeld VL, Kayser C. Risk factors for body composition abnormalities in systemic sclerosis. Clin Rheumatol  2013; 32(7): 1037-44.
 [http://dx.doi.org/10.1007/s10067-013-2235-1] [PMID: 23549639]

[21]
Mok CC, Chan PT, Chan KL, Ma KM. Prevalence and risk factors of low bone mineral density in Chinese patients with systemic sclerosis: A case control study. Rheumatology (Oxford)  2013; 52(2): 296-303.
 [http://dx.doi.org/10.1093/rheumatology/kes240] [PMID: 23006511]

[22]
Ibn Yacoub Y, Amine B, Laatiris A, Wafki F, Znat F, Hajjaj-Hassouni N. Bone density in Moroccan women with systemic scleroderma and its relationships with disease-related parameters and vitamin D status. Rheumatol Int  2012; 32(10): 3143-8.
 [http://dx.doi.org/10.1007/s00296-011-2150-1] [PMID: 21947376]

[23]
Shinjo SK, Bonfá E, de Falco Caparbo V, Pereira RM. Low bone mass in juvenile onset sclerosis systemic: The possible role for 25-hydroxyvitamin D insufficiency. Rheumatol Int  2011; 31(8): 1075-80.
 [http://dx.doi.org/10.1007/s00296-010-1421-6] [PMID: 20336459]

[24]
Omair MA, McDonald-Blumer H, Johnson SR. Bone disease in systemic sclerosis: Outcomes and associations. Clin Exp Rheumatol  2014; 32(6) (Suppl. 86): S-28-32.
 [PMID: 24321499]

[25]
Atteritano M, Sorbara S, Bagnato G, et al. Bone mineral density, bone turnover markers and fractures in patients with systemic sclerosis: A case control study. PLoS One  2013; 8(6): e66991.
 [http://dx.doi.org/10.1371/journal.pone.0066991] [PMID: 23818972]

[26]
Koumakis E, Avouac J, Winzenrieth R, et al. Trabecular bone score in female patients with systemic sclerosis: Comparison with rheumatoid arthritis and influence of glucocorticoid exposure. J Rheumatol  2015; 42(2): 228-35.
 [http://dx.doi.org/10.3899/jrheum.140752] [PMID: 25448793]

[27]
Fauny M, Bauer E, Albuisson E, et al. Vertebral fracture prevalence and measurement of the scanographic bone attenuation coefficient on CT-scan in patients with systemic sclerosis. Rheumatol Int  2018; 38(10): 1901-10.
 [http://dx.doi.org/10.1007/s00296-018-4139-5] [PMID: 30132216]

[28]
Lai CC, Wang SH, Chen WS, et al. Increased risk of osteoporotic fractures in patients with systemic sclerosis: A nationwide population-based study. Ann Rheum Dis  2015; 74(7): 1347-52.
 [http://dx.doi.org/10.1136/annrheumdis-2013-204832] [PMID: 24532679]

[29]
Kanis JA, Cooper C, Rizzoli R, Reginster JY. Scientific advisory board of the european society for clinical and economic aspects of osteoporosis and osteoarthritis (ESCEO) and the committees of scientific advisors and national societies of the International Osteoporosis Foundation (IOF). Executive summary of the European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Calcif Tissue Int  2019; 104(3): 235-8.
 [http://dx.doi.org/10.1007/s00223-018-00512-x] [PMID: 30796490]

[30]
Greenblatt MB, Tsai JN, Wein MN. Bone turnover markers in the diagnosis and monitoring of metabolic bone disease. Clin Chem  2017; 63(2): 464-74.
 [http://dx.doi.org/10.1373/clinchem.2016.259085] [PMID: 27940448]

[31]
Hunzelmann N, Risteli J, Risteli L, et al. Circulating type I collagen degradation products: a new serum marker for clinical severity in patients with scleroderma? Br J Dermatol  1998; 139(6): 1020-5.
 [http://dx.doi.org/10.1046/j.1365-2133.1998.02558.x] [PMID: 9990365]

[32]
Allanore Y, Borderie D, Lemaréchal H, Cherruau B, Ekindjian OG, Kahan A. Correlation of serum collagen I carboxyterminal telopeptide concentrations with cutaneous and pulmonary involvement in systemic sclerosis. J Rheumatol  2003; 30(1): 68-73.
 [PMID: 12508392]

[33]
Istok R, Czirják L, Lukác J, Stancíková M, Rovenský J. Increased urinary pyridinoline cross-link compounds of collagen in patients with systemic sclerosis and Raynaud’s phenomenon. Rheumatology (Oxford)  2001; 40(2): 140-6.
 [http://dx.doi.org/10.1093/rheumatology/40.2.140] [PMID: 11257149]

[34]
Wang RN, Green J, Wang Z, et al. Bone Morphogenetic Protein (BMP) signaling in development and human diseases. Genes Dis  2014; 1(1): 87-105.
 [http://dx.doi.org/10.1016/j.gendis.2014.07.005] [PMID: 25401122]

[35]
Montagnana M, Lippi G, Danese E, Guidi GC. The role of osteoprotegerin in cardiovascular disease. Ann Med  2013; 45(3): 254-64.
 [http://dx.doi.org/10.3109/07853890.2012.727019] [PMID: 23110639]

[36]
Forde H, Harper E, Davenport C, et al. The beneficial pleiotropic effects of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) within the vasculature: A review of the evidence. Atherosclerosis  2016; 247: 87-96.
 [http://dx.doi.org/10.1016/j.atherosclerosis.2016.02.002] [PMID: 26878368]

[37]
Zhou M, Li S, Pathak JL. Pro-inflammatory cytokines and osteocytes. Curr Osteoporos Rep  2019; 17(3): 97-104.
 [http://dx.doi.org/10.1007/s11914-019-00507-z] [PMID: 30915637]

[38]
Fernández-Roldán C, Genre F, López-Mejías R, et al. Sclerostin serum levels in patients with systemic autoimmune diseases. Bonekey Rep  2016; 5: 775.
 [http://dx.doi.org/10.1038/bonekey.2016.2] [PMID: 26909149]

[39]
Daoussis D, Papachristou D J, Dimitroulas T, et al. Dickkopf-1 is downregulated early and universally in the skin of patients with systemic sclerosis despite normal circulating levels. Clin Exp Rheumatol  2018; (36)113(4): 45-9.

[40]
Ruaro B, Casabella A, Paolino S, et al. Dickkopf-1 (Dkk-1) serum levels in systemic sclerosis and rheumatoid arthritis patients: Correlation with the Trabecular Bone Score (TBS). Clin Rheumatol  2018; 37(11): 3057-62.
 [http://dx.doi.org/10.1007/s10067-018-4322-9] [PMID: 30291470]

[41]
van Leeuwen JP, van Driel M, van den Bemd GJ, Pols HA. Vitamin D control of osteoblast function and bone extracellular matrix mineralization. Crit Rev Eukaryot Gene Expr  2001; 11(1-3): 199-226.
 [http://dx.doi.org/10.1615/CritRevEukarGeneExpr.v11.i1-3.100] [PMID: 11693961]

[42]
Berardi S, Giardullo L, Corrado A, Cantatore FP. Vitamin D and connective tissue diseases. Inflamm Res  2020; 69(5): 453-62.
 [http://dx.doi.org/10.1007/s00011-020-01337-x] [PMID: 32172354]

[43]
Sampaio-Barros MM, Takayama L, Sampaio-Barros PD, Bonfá E, Pereira RM. Low vitamin D serum levels in diffuse systemic sclerosis: A correlation with worst quality of life and severe capillaroscopic findings. Rev Bras Reumatol Engl Ed  2016; 56(4): 337-44.
 [http://dx.doi.org/10.1016/j.rbre.2016.05.006] [PMID: 27476627]

[44]
Braun-Moscovici Y, Furst DE, Markovits D, et al. Vitamin D, parathyroid hormone, and acroosteolysis in systemic sclerosis. J Rheumatol  2008; 35(11): 2201-5.
 [http://dx.doi.org/10.3899/jrheum.071171] [PMID: 18843781]

[45]
Samelson EJ, Broe KE, Xu H, et al. Cortical and trabecular bone microarchitecture as an independent predictor of incident fracture risk in older women and men in the Bone Microarchitecture International Consortium (BoMIC): A prospective study. Lancet Diabetes Endocrinol  2019; 7(1): 34-43.
 [http://dx.doi.org/10.1016/S2213-8587(18)30308-5] [PMID: 30503163]

[46]
Horváth Á, Végh E, Pusztai A, et al. Complex assessment of bone mineral density, fracture risk, vitamin D status, and bone metabolism in Hungarian systemic sclerosis patients. Arthritis Res Ther  2019; 21(1): 274.
 [http://dx.doi.org/10.1186/s13075-019-2072-y] [PMID: 31823821]

[47]
Sampaio-Barros MM, Alvarenga JC, Takayama L, Assad APL, Sampaio-Barros PD, Pereira RMR. Distal radius and tibia bone microarchitecture impairment in female patients with diffuse systemic sclerosis. Osteoporos Int  2019; 30(8): 1679-91.
 [http://dx.doi.org/10.1007/s00198-019-04965-0] [PMID: 31030240]

[48]
Marot M, Valéry A, Esteve E, et al. Prevalence and predictive factors of osteoporosis in systemic sclerosis patients: A case-control study. Oncotarget  2015; 6(17): 14865-73.
 [http://dx.doi.org/10.18632/oncotarget.3806] [PMID: 25944694]

[49]
Shevroja E, Lamy O, Kohlmeier L, Koromani F, Rivadeneira F, Hans D. Use of Trabecular Bone Score (TBS) as a complementary approach to dual-energy X-ray absorptiometry (DXA) for fracture risk assessment in clinical practice. J Clin Densitom  2017; 20(3): 334-45.
 [http://dx.doi.org/10.1016/j.jocd.2017.06.019] [PMID: 28734710]

[50]
Shah AA, Wigley FM. Often forgotten manifestations of systemic sclerosis. Rheum Dis Clin North Am  2008; 34(1): 221-38. ix.
 [http://dx.doi.org/10.1016/j.rdc.2007.10.002] [PMID: 18329542]

[51]
Avouac J, Mogavero G, Guerini H, et al. Predictive factors of hand radiographic lesions in systemic sclerosis: A prospective study. Ann Rheum Dis  2011; 70(4): 630-3.
 [http://dx.doi.org/10.1136/ard.2010.134304] [PMID: 21131648]

[52]
Siao-Pin S, Damian LO, Muntean LM, Rednic S. Acroosteolysis in systemic sclerosis: An insight into hypoxia-related pathogenesis. Exp Ther Med  2016; 12(5): 3459-63.
 [http://dx.doi.org/10.3892/etm.2016.3782] [PMID: 27882179]

[53]
Knowles HJ, Athanasou NA. Acute hypoxia and osteoclast activity: A balance between enhanced resorption and increased apoptosis. J Pathol  2009; 218(2): 256-64.
 [http://dx.doi.org/10.1002/path.2534] [PMID: 19291710]

[54]
Nakagawa M, Kaneda T, Arakawa T, et al. Vascular Endothelial Growth Factor (VEGF) directly enhances osteoclastic bone resorption and survival of mature osteoclasts. FEBS Lett  2000; 473(2): 161-4.
 [http://dx.doi.org/10.1016/S0014-5793(00)01520-9] [PMID: 10812066]

[55]
Flower VA, Barratt SL, Ward S, Pauling JD. The role of vascular endothelial growth factor in systemic sclerosis. Curr Rheumatol Rev  2019; 15(2): 99-109.
 [http://dx.doi.org/10.2174/1573397114666180809121005] [PMID: 30091416]

[56]
Park JK, Fava A, Carrino J, Del Grande F, Rosen A, Boin F. Association of acroosteolysis with enhanced osteoclastogenesis and higher blood levels of vascular endothelial growth factor in systemic sclerosis. Arthritis Rheumatol  2016; 68(1): 201-9.
 [http://dx.doi.org/10.1002/art.39424] [PMID: 26361270]

[57]
Meyer O. CREST syndrome. Ann Med Interne (Paris)  2002; 153(3): 183-8.
 [PMID: 12218901]

[58]
Gutierrez A Jr, Wetter DA. Calcinosis cutis in autoimmune connective tissue diseases. Dermatol Ther  2012; 25(2): 195-206.
 [http://dx.doi.org/10.1111/j.1529-8019.2012.01492.x] [PMID: 22741938]

[59]
Pachman LM, Veis A, Stock S, et al. Composition of calcifications in children with juvenile dermatomyositis: Association with chronic cutaneous inflammation. Arthritis Rheum  2006; 54(10): 3345-50.
 [http://dx.doi.org/10.1002/art.22158] [PMID: 17009308]

[60]
Elhai M, Guerini H, Bazeli R, et al. Ultrasonographic hand features in systemic sclerosis and correlates with clinical, biologic, and radio-graphic findings. Arthritis Care Res (Hoboken)  2012; 64(8): 1244-9.
 [PMID: 22422556]

[61]
Cruz-Domínguez MP, García-Collinot G, Saavedra MA, et al. Clinical, biochemical, and radiological characterization of the calcinosis in a cohort of Mexican patients with systemic sclerosis. Clin Rheumatol  2017; 36(1): 111-7.
 [http://dx.doi.org/10.1007/s10067-016-3412-9] [PMID: 27718018]

[62]
Sujau I, Ng CT, Sthaneshwar P, et al. Clinical and autoantibody profile in systemic sclerosis: Baseline characteristics from a West Malaysian cohort. Int J Rheum Dis  2015; 18(4): 459-65.
 [http://dx.doi.org/10.1111/1756-185X.12322] [PMID: 24618222]

[63]
Pai S, Hsu V. Are there risk factors for scleroderma-related calcinosis? Mod Rheumatol  2018; 28(3): 518-22.
 [http://dx.doi.org/10.1080/14397595.2017.1349594] [PMID: 28722530]

[64]
Baron M, Pope J, Robinson D, et al. Calcinosis is associated with digital ischaemia in systemic sclerosis-a longitudinal study. Rheumatology (Oxford)  2016; 55(12): 2148-55.
 [http://dx.doi.org/10.1093/rheumatology/kew313] [PMID: 27593964]

[65]
Morgan ND, Shah AA, Mayes MD, et al. Clinical and serological features of systemic sclerosis in a multicenter African American cohort: Analysis of the genome research in African American scleroderma patients clinical database. Medicine (Baltimore)  2017; 96(51): e8980.
 [http://dx.doi.org/10.1097/MD.0000000000008980] [PMID: 29390428]

[66]
Valenzuela A, Baron M, Herrick AL, et al. Calcinosis is associated with digital ulcers and osteoporosis in patients with systemic sclerosis: A scleroderma clinical trials consortium study. Semin Arthritis Rheum  2016; 46(3): 344-9.
 [http://dx.doi.org/10.1016/j.semarthrit.2016.05.008] [PMID: 27371996]

[67]
Boulman N, Slobodin G, Rozenbaum M, Rosner I. Calcinosis in rheumatic diseases. Semin Arthritis Rheum  2005; 34(6): 805-12.
 [http://dx.doi.org/10.1016/j.semarthrit.2005.01.016] [PMID: 15942915]

[68]
Termine JD, Kleinman HK, Whitson SW, Conn KM, McGarvey ML, Martin GR. Osteonectin, a bone-specific protein linking mineral to collagen. Cell  1981; 26(1 Pt 1): 99-105.
 [http://dx.doi.org/10.1016/0092-8674(81)90037-4] [PMID: 7034958]

[69]
Davies CA, Jeziorska M, Freemont AJ, Herrick AL. Expression of osteonectin and matrix Gla protein in scleroderma patients with and without calcinosis. Rheumatology (Oxford)  2006; 45(11): 1349-55.
 [http://dx.doi.org/10.1093/rheumatology/kei277] [PMID: 17050587]

[70]
Davies CA, Herrick AL, Cordingley L, Freemont AJ, Jeziorska M. Expression of advanced glycation end products and their receptor in skin from patients with systemic sclerosis with and without calcinosis. Rheumatology (Oxford)  2009; 48(8): 876-82.
 [http://dx.doi.org/10.1093/rheumatology/kep151] [PMID: 19542215]

[71]
Niida S, Kondo T, Hiratsuka S, et al. VEGF receptor 1 signaling is essential for osteoclast development and bone marrow formation in colony-stimulating factor 1-deficient mice. Proc Natl Acad Sci USA  2005; 102(39): 14016-21.
 [http://dx.doi.org/10.1073/pnas.0503544102] [PMID: 16172397]

[72]
Utting JC, Flanagan AM, Brandao-Burch A, Orriss IR, Arnett TR. Hypoxia stimulates osteoclast formation from human peripheral blood. Cell Biochem Funct  2010; 28(5): 374-80.
 [http://dx.doi.org/10.1002/cbf.1660] [PMID: 20556743]

[73]
Montesi M, Jähn K, Bonewald L, Stea S, Bordini B, Beraudi A. Hypoxia mediates osteocyte ORP150 expression and cell death in vitro. Mol Med Rep  2016; 14(5): 4248-54.
 [http://dx.doi.org/10.3892/mmr.2016.5790] [PMID: 27748851]

[74]
Hinoi E, Ochi H, Takarada T, et al. Positive regulation of osteoclastic differentiation by growth differentiation factor 15 upregulated in osteocytic cells under hypoxia. J Bone Miner Res  2012; 27(4): 938-49.
 [http://dx.doi.org/10.1002/jbmr.1538] [PMID: 22190281]

[75]
Genetos DC, Toupadakis CA, Raheja LF, et al. Hypoxia decreases sclerostin expression and increases Wnt signaling in osteoblasts. J Cell Biochem  2010; 110(2): 457-67.
 [http://dx.doi.org/10.1002/jcb.22559] [PMID: 20336693]

[76]
Stegen S, Stockmans I, Moermans K, et al. Osteocytic oxygen sensing controls bone mass through epigenetic regulation of sclerostin. Nat Commun  2018; 9(1): 2557.
 [http://dx.doi.org/10.1038/s41467-018-04679-7] [PMID: 29967369]

[77]
O’Reilly S, Ciechomska M, Cant R, van Laar JM. Interleukin-6 (IL-6) trans signaling drives a STAT3-dependent pathway that leads to hyperactive transforming growth factor-β (TGF-β) signaling promoting SMAD3 activation and fibrosis via Gremlin protein. J Biol Chem  2014; 289(14): 9952-60.
 [http://dx.doi.org/10.1074/jbc.M113.545822] [PMID: 24550394]

[78]
Krock BL, Skuli N, Simon MC. Hypoxia-induced angiogenesis: Good and evil. Genes Cancer  2011; 2(12): 1117-33.
 [http://dx.doi.org/10.1177/1947601911423654] [PMID: 22866203]

[79]
Distler JH, Akhmetshina A, Schett G, Distler O. Monocyte chemoattractant proteins in the pathogenesis of systemic sclerosis. Rheumatology (Oxford)  2009; 48(2): 98-103.
 [http://dx.doi.org/10.1093/rheumatology/ken401] [PMID: 18984611]

[80]
Yamamoto T. Pathogenic role of CCL2/MCP-1 in scleroderma. Front Biosci  2008; 13(13): 2686-95.
 [http://dx.doi.org/10.2741/2875] [PMID: 17981743]

[81]
Bellando Randone S, George J, Mazzotta C, et al. Angiostatic and angiogenic chemokines in systemic sclerosis: An overview. J Scleroderma Relat Disord  2016; 2(1): 1-10.
 [http://dx.doi.org/10.5301/jsrd.5000226]

[82]
Mulholland BS, Forwood MR, Morrison NA. Monocyte chemoattractant protein-1 (MCP-1/CCL2) drives activation of bone remodelling and skeletal metastasis. Curr Osteoporos Rep  2019; 17(6): 538-47.
 [http://dx.doi.org/10.1007/s11914-019-00545-7] [PMID: 31713180]

[83]
Valenzuela A, Song P, Chung L. Calcinosis in scleroderma. Curr Opin Rheumatol  2018; 30(6): 554-61.
 [http://dx.doi.org/10.1097/BOR.0000000000000539] [PMID: 30124603]

[84]
Pietschmann P, Mechtcheriakova D, Meshcheryakova A, Föger-Samwald U, Ellinger I. Immunology of osteoporosis: A mini-review. Gerontology  2016; 62(2): 128-37.
 [http://dx.doi.org/10.1159/000431091] [PMID: 26088283]

[85]
Arnson Y, Amital H, Agmon-Levin N, et al. Serum 25-OH vitamin D concentrations are linked with various clinical aspects in patients with systemic sclerosis: A retrospective cohort study and review of the literature. Autoimmun Rev  2011; 10(8): 490-4.
 [http://dx.doi.org/10.1016/j.autrev.2011.02.002] [PMID: 21320645]

[86]
Artaza JN, Norris KC. Vitamin D reduces the expression of collagen and key profibrotic factors by inducing an antifibrotic phenotype in mesenchymal multipotent cells. J Endocrinol  2009; 200(2): 207-21.
 [http://dx.doi.org/10.1677/JOE-08-0241] [PMID: 19036760]
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DOI https://dx.doi.org/10.2174/1573397118666220218112703	Print ISSN 1573-3971
Publisher Name Bentham Science Publisher	Online ISSN 1875-6360
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Bone Metabolism Alterations in Systemic Sclerosis: An Insight into Bone Disease in SSc: From the Radiographic Findings to their Potential Pathogenesis and Outcome

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