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Mechanisms of Bone Fragility: from Osteogenesis Imperfecta to Secondary Osteoporosis

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Mechanisms of Bone Fragility: from Osteogenesis Imperfecta to Secondary Osteoporosis International Journal of Molecular Sciences Review Mechanisms of Bone Fragility: From Osteogenesis Imperfecta to Secondary Osteoporosis Ahmed El-Gazzar and Wolfgang Högler * Department of Paediatrics and Adolescent Medicine, Johannes Kepler University Linz, Krankenhausstraße 26-30, 4020 Linz, Austria; [email protected] * Correspondence: [email protected]; Tel.: +43-(0)5-7680-84-22001; Fax: +43-(0)5-7680-84-22004 Abstract: Bone material strength is determined by several factors, such as bone mass, matrix composi- tion, mineralization, architecture and shape. From a clinical perspective, bone fragility is classified as primary (i.e., genetic and rare) or secondary (i.e., acquired and common) osteoporosis. Understanding the mechanism of rare genetic bone fragility disorders not only advances medical knowledge on rare diseases, it may open doors for drug development for more common disorders (i.e., postmenopausal osteoporosis). In this review, we highlight the main disease mechanisms underlying the development of human bone fragility associated with low bone mass known to date. The pathways we focus on are type I collagen processing, WNT-signaling, TGF-ß signaling, the RANKL-RANK system and the osteocyte mechanosensing pathway. We demonstrate how the discovery of most of these pathways has led to targeted, pathway-specific treatments. Keywords: bone fragility; type I collagen; post-translational modifications; extracellular matrix; osteogenesis imperfecta; Juvenile Paget disease; osteomalacia; osteopetrosis 1. Introduction Citation: El-Gazzar, A.; Högler, W. Mechanisms of Bone Fragility: From Developing bones consist of cartilaginous joints, the epiphysis, the growth plate carti- Osteogenesis Imperfecta to Secondary lage with adjacent osteogenesis and the cortical and cancellous bone mineralized structure. Osteoporosis. Int. J. Mol. Sci. 2021, 22, Bone tissue contains three distinct cell types: (i) the osteoblasts, derived from mesenchy- 625. https://doi.org/10.3390/ijms mal cells, which deposit new bone tissue; (ii) osteoclasts, derived from bone marrow 22020625 hematopoietic precursor cells, which break down bone matrix; and (iii) osteocytes (former osteoblasts) which orchestrate the activity of osteoblasts and osteoclasts as a response to Received: 22 December 2020 mechanical strain [1]. The extracellular matrix of bone tissue is composed of inorganic Accepted: 7 January 2021 minerals, collagen, water, non-collagenous proteins and lipids. Bone fragility can originate Published: 10 January 2021 from alterations in all these components, be it the genetic blueprint, mechanical loading, in- sufficient remodeling at old age, estrogen deficiency or chronic medical conditions affecting Publisher’s Note: MDPI stays neu- bone accrual, structure or composition. tral with regard to jurisdictional clai- Traditionally, bone fragility is understood as resulting from reduced bone mass, or ms in published maps and institutio- from defects in bone matrix composition or mineralization. Medical research has unveiled nal affiliations. many monogenic bone fragility conditions, yet their mechanisms of disease remain incom- pletely understood. In fact, they continue holding secrets which may open doors for drug developments in rare and common osteoporosis. In this review, we highlight the main and Copyright: © 2021 by the authors. Li- some exemplary mechanisms underlying human bone fragility associated with reduced censee MDPI, Basel, Switzerland. bone mass. This article is an open access article Due to word limitations, we are not including groups of conditions associated with distributed under the terms and con- bone fragility, such as high bone mass disorders (osteopetrosis) and conditions of bone ditions of the Creative Commons At- demineralization (rickets and osteomalacia). In osteopetrosis, fragility is caused by high tribution (CC BY) license (https:// mineralization density with lack of bone repair [2], and in the demineralization group, creativecommons.org/licenses/by/ fragility is caused by insufficient bone mineral supply or deposition [3]. 4.0/). Int. J. Mol. Sci. 2021, 22, 625. https://doi.org/10.3390/ijms22020625 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 20 2. Genetic Causes of Bone Fragility Int. J. Mol. Sci. 2021, 22, 625 2 of 18 2.1. Primary Osteoporosis Affecting Collagen (Osteogenesis Imperfecta) 2.1.1. Clinical Symptoms and Classification 2. GeneticRecurrent Causes limb ofand Bone vertebral Fragility fractures are typical for patients with osteogenesis im- perfecta2.1. Primary (OI). OI, Osteoporosis also known Affecting as brittle Collagen bone (Osteogenesisdisease, is an Imperfecta)inherited disorder of connective tissue2.1.1. that Clinical has Symptomsa wide clinical and Classificationand genetic heterogeneity. OI is a rare disorder, with an incidenceRecurrent of one in limb 10,000–20,000 and vertebral births fractures [4]. From are a typicalbone material for patients perspective, with osteogenesis OI is char- acterizedimperfecta by (OI).low bone OI, also mass known and increased as brittle bone bone disease, mineralization is an inherited density, disorder which ofcauses connective brit- tlenesstissue (Figure that has 1), a recurrent wide clinical fractures and and genetic skelet heterogeneity.al deformities, OI but is also a rare extra-skeletal disorder, with man- an ifestations.incidence The of one latter in include 10,000–20,000 blue sclerae, births dentinogenesis [4]. From a bone imperfecta, material joint perspective, laxity, hearing OI is losscharacterized as well as cranial by low malformations bone mass and (i.e., increased basilar invagination) bone mineralization and pulmonary density, which hypoplasia causes withbrittleness reduced (Figure lung 1capacity), recurrent in severe fractures cases. and Depending skeletal deformities, on clinical but severity, also extra-skeletal mobility is mildlymanifestations. to severely The impaired. latter include Fractures blue ar sclerae,e particularly dentinogenesis common imperfecta,in childhood joint but laxity, in- creasedhearing fracture loss as risk well persists as cranial throughout malformations life. (i.e., basilar invagination) and pulmonary hypoplasia with reduced lung capacity in severe cases. Depending on clinical severity, mobility is mildly to severely impaired. Fractures are particularly common in childhood but increased fracture risk persists throughout life. Figure 1. The extremes of bone mineralization density distribution (BMDD): bone tissue in patients with OI has increased Figuremineralization 1. The extremes density. of This bone is mineralization due to the irregular density collagen distribution fibers (BMDD): and their bone wider tissue spatial in patients distribution with which OI has allows increased more mineralizationhydroxyapatite density. deposition. This is Also due depicted to the irregular is the opposite: collagen lowfibers tissue and mineralizationtheir wider spatial density distribution in patients which with allows osteomalacia. more hydroxyapatite deposition. Also depicted is the opposite: low tissue mineralization density in patients with osteomalacia. Approximately ~85–90% of OI patients harbor heterozygous mutations in genes encodingApproximately type I collagen ~85–90%COL1A1 of OI patients[MIM: 120150]harbor heterozygous or COL1A2 [MIM: mutations 120160], in genes which en- are codingthe genes type thatI collagen encode COL1A1 the α1(I) [MIM: and 120150]α2(I) chain or COL1A2 of type [MIM: I collagen, 120160], respectively. which are the The genesremaining that encode ~10–15% the α harbor1(I) and mostly α2(I) recessivechain of type mutations I collagen, in various respectively. genes, The which remaining were all ~10–15%identified harbor after mostly 2006. Whilerecessive these mutations discoveries in various have contributed genes, which to were ourunderstanding all identified afterof the 2006. genetic While basis these of discoveries OI, many have molecular contributed disease to mechanisms our understanding caused of by the these genetic gene basismutations of OI, many are incompletely molecular disease understood. mechanis Thusms far, caused 24+ genes by these have gene been mutations identified toare cause in- completelyOI (Table1 understood.). These include Thus IFITM5far, 24+ [genes5,6] [MIM: have been 614757], identifiedSERPINF1 to cause[7] [MIM: OI (Table 172860], 1). TheseCRTAP include[8] [MIM: IFITM5 605497], [5,6] [MIM:LEPRE1 614757],[9] [MIM: SERPINF1 610339], [7]P3H1 [MIM:[10 172860],] [MIM: CRTAP 610339], [8]PPIB [MIM:[11 ] 605497],[MIM: 123841],LEPRE1SERPINH1 [9] [MIM: [610339],12] [MIM: P3H1 600943], [10] [MIM:FKBP10 610339],[13] [MIM: PPIB 607063], [11] [MIM:SP7 [ 14123841],] [MIM: SERPINH1606633], BMP1 [12] [MIM:[15] [MIM: 600943], 112264], FKBP10TMEM38B [13] [MIM:[16 607063],] [MIM: SP7 611236], [14] [MIM:WNT1 606633],[17,18 ]BMP1 [MIM: [15]164820], [MIM:CREB3L1 112264], TMEM38B[19] [MIM: [16] 616215], [MIM:SPARC 611236],[ 20WNT1] [MIM: [17,18] 182120], [MIM:FAM46A 164820], [CREB3L121] [MIM: [19]611357], [MIM:MBTPS2 616215], SPARC[22] [MIM: [20] [MIM: 300294], 182120],MESD FAM46A[23] [MIM: [21] [MIM: 607783], 611357],SEC24D MBTPS2[24] [MIM: [22] [MIM:607186], 300294],CCDC134 MESD[25] [23] [MIM: [MIM: 618788], 607783],P4HB SEC24D[26] [MIM: [24] 176790], [MIM:PLOD2 607186],[27 CCDC134] [MIM: 601865], [25] [MIM:PLS3 [618788],28] [MIM: P4HB 300131] [26]and [MIM:KDELR2 176790],[MIM: PLOD2 609024] [27] [ 29[MIM:]. These 601865], genes PLS3 play a[28] critical
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