177:2

E Boudin and W Van Hul Genetics of human bone 177:2 R69–R83 Review formation

MECHANISMS IN ENDOCRINOLOGY Genetics of human bone formation

Eveline Boudin and Wim Van Hul Correspondence Center of Medical Genetics, University of Antwerp, Antwerp, Belgium should be addressed to W Van Hul Email [email protected]

Abstract

Throughout life, bone is continuously remodelled to be able to fulfil its multiple functions. The importance of strictly regulating the bone remodelling process, which is defined by the sequential actions of osteoclasts and osteoblasts, is shown by a variety of disorders with abnormalities in bone mass and strength. The best known and most common example of such a disorder is osteoporosis, which is marked by a decreased bone mass and strength that consequently results in an increased fracture risk. As osteoporosis is a serious health problem, a large number of studies focus on elucidating the aetiology of the disease as well as on the identification of novel therapeutic targets for the treatment of osteoporotic patients. These studies have demonstrated that a large amount of variation in bone mass and strength is often influenced by genetic variation in genes encoding important regulators of bone homeostasis. Throughout the years, studies into the genetic causes of osteoporosis as well as several rare monogenic disorders with abnormal high or low bone mass and strength have largely increased the knowledge on regulatory pathways important for bone resorption and formation. This review gives an overview of genes and pathways that are important for the regulation of bone formation and that are identified through their involvementp in monogenic and complex disorders with abnormal bone mass. Furthermore, novel bone-forming strategies for the treatment of osteoporosis that resulted from these discoveries, such as antibodies against sclerostin, are discussed as well. European Journal European of Endocrinology European Journal of Endocrinology (2017) 177, R69–R83

Introduction

The human skeleton has several functions such as The osteocytes, differentiated from osteoblasts and support and protection of soft tissue. To maintain bone located in the mineralised bone have, together with strength, skeletal bones are subjected to continuous several signalling pathways, an important role in the bone remodelling. During the bone remodelling process, regulation of bone remodelling (1, 2, 3). Disturbance of the activity of the bone-resorbing osteoclasts and the balance between bone resorption and bone formation bone-forming osteoblasts is well balanced and strictly can result in pathological abnormalities in bone mineral regulated to maintain bone mass and bone strength. density (BMD).

Invited Author’s profile Wim Van Hul, Msc, PhD, is full-time Professor of Molecular Biology and Genetics at the University of Antwerp, Belgium. He is in charge of a research team studying genetic factors underlying skeletal disorders and obesity. They were successful in identifying and characterising several disease-causing genes including the SOST gene encoding the sclerostin protein.

www.eje-www.eje-online.orgonline.org © 2017 European Society of Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/EJE-16-0990 Printed in Great Britain

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Osteoporosis is the most prevalent metabolic bone bone mass and strength. These so-called monogenic bone disease and is marked by a decreased BMD that results in disorders are usually rare disorders with a clear mode of increased fracture risk. It has, due to its high prevalence, inheritance. Although the prevalence of these disorders hospitalisation, morbidity and mortality, a high socio- is rare, a large number of different monogenic disorders economic burden, which makes prevention, diagnosis have been described. Depending on the genetic defect, and treatment an important research topic (4). BMD is a disorders with an increased fracture risk due to low BMD skeletal trait that is widely used as a surrogate phenotype or impaired microarchitecture of the bone tissue and for several common (for example, osteoporosis) and rare disorders with increased bone mass can be distinguished. bone disorders. It is reported as a T- or Z-score with the Based on their function, we can classify the majority of T-score representing the number of standard deviations these disease-causing genes in one of three major signalling above or below the average peak bone mass of young pathways regulating bone formation, namely collagen 1 adults, whereas the Z-score represents the number of biosynthesis, WNT signalling and TGFβ signalling. Finally, standard deviations above or below the average BMD of for some other disease-causing genes, the function in bone an individual of the same age (5, 6). A T-score between formation is still unclear or independent of the previously −1 and 1 is considered normal, whereas a score below or mentioned signalling pathways. equal to −2.5 indicates osteoporosis (7). Variation in BMD is caused by a combination of Collagen type 1 metabolism environmental and genetic factors. Heritability studies have shown that the genetic impact on BMD can vary Collagen, more specifically collagen type 1, is the most between different skeletal sites, but overall, 50–85% of important and abundant organic component of the the variation in BMD is due to genetic factors (8, 9, 10, extracellular bone matrix that provides the bone strength 11, 12). In most cases, the genetic impact is determined and flexibility. Collagen type 1 in bone consists of by genetic variation in a large amount of genes with three polypeptide chains (α-chains) that form a triple- small effect sizes. In a minority of cases, one mutation helix structure (18, 19). Mutations in one of the genes in one gene has a major effect on bone mass or bone responsible for collagen type 1 synthesis and assembly strength. Although this is only true in a small number of p can consequently be the cause of brittle bone disease cases, identification of these genes largely increased the or alternatively called osteogenesis imperfecta (OI). knowledge of pathways that regulate bone homeostasis OI is the collective name of a clinically and genetically (4, 8, 13). Furthermore, genome-wide association studies heterogeneous group of connective tissue disorders. In European Journal European of Endocrinology (GWAS) that aim to identify genes and variants involved addition to low bone mass and fractures, patients with in the regulation of BMD in the general population have OI often suffer from other connective tissue symptoms confirmed the importance of the same pathways in the such as blue sclerae and dentinogenesis imperfecta (19, regulation of bone homeostasis (14, 15, 16). 20, 21). Radiographically, five different OI types can The list with monogenic skeletal disorders is extensive be distinguished (OI type I–V). OI type II is the most and is reviewed in 2015 by Bonafe in the nosology severe form and often results in perinatal death, whereas of skeletal disorders that includes 364 different genes OI types I and IV are the mildest non-deforming types involved in the aetiology of 436 different skeletal disorders (17, 21). Type V is the most recently identified type of (17). In this review, we will only focus on a small subset of OI that is diagnosed in less than 5% of the OI cases (22, genes and pathways that are known to be involved in the 23). In around 90% of the osteogenesis imperfecta cases, regulation of bone formation and that are identified either autosomal dominant (AD) mutations in COL1A1 and by studying human monogenic bone disorders with high COL1A2 are identified. Depending on the nature and or low BMD or by performing genome-wide association localisation of the mutation, different types of OI (types studies in large cohorts in an attempt to explain the I–IV) can be caused by mutations in these genes (Table 1) complex genetic architecture of BMD. (24). The remaining 10% of the OI type I–IV cases are autosomal recessive (AR), and throughout the years, Monogenic bone disorders mutations in a total of 14 different genes are identified (4, 8, 25). The majority of these genes, namely CRTAP, As mentioned in the introduction, in a small number LEPREI1, PLOD2, CREB3L1, PPIB, SERPINH1, SERPINF1, of cases mutations in one gene have a major effect on FKBP10, TMEM38B, MBTPS2, SPARC and BMP1 are directly

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Table 1 Overview of disease-causing genes involved in human bone formation for monogenic bone disorders marked by high or low bone mass.

Pathway Bone mass Gene Disorder Collagen type 1 metabolism Low bone mass Col1A1 OI type I, II, III, IV Col1A2 OI type I, II, III, IV CRTAP OI type II, III, IV LEPRE1 OI type II, III PPIB OI type II, III, IV BMP1 OI type III FKBP10 OI type III, IV; Bruck syndrome type I PLOD2 OI type III; Bruck syndrome type II SERPINH1 OI type III CREB3L1 OI type III TMEM38B OI type III SERPINF1 OI type III, IV MBTPS2 X-linked OI SPARC OI type IV P4HB Cole-Carpenter syndrome type I, AD SEC24D Cole-Carpenter syndrome type II, AR WNT signalling Low bone mass WNT1 OI type II, IV; Juvenile idiopathic osteoporosis LRP5 Juvenile idiopathic osteoporosis; Osteoporosis pseudoglioma High bone mass LRP5 HBM phenotype, endosteal hyperostosis, Worth disease, osteosclerosis SOST Sclerosteosis; Van Buchem disease; Craniodiaphyseal dysplasia LRP4 Sclerosteosis WTX Osteopathia striata TGFβ signalling High bone mass TGFβ1 Camurati-Engelmann disease LEMD3 Osteopoikilosis; Buschke–Ollendorff syndrome Osteogenic cell differentiation Low bone mass Sp7 OI type III, IV High bone mass GJA1 Craniometaphyseal dysplasia, AR Mineralization Low bone mass IFITM5 OI type V High bone mass ANKH p Craniometaphyseal dysplasia, AD FAM20C Raine syndrome Unknown Low bone mass PLS3 X-linked osteoporosis

European Journal European of Endocrinology or indirectly involved in the collagen 1 synthesis and involved in collagen 1 biosynthesis, as disease-causing assembly (Fig. 1 and Table 1) (19, 20, 25, 26, 27, 28, 29, 30, genes for AD and AR forms of Cole-Carpenter disease 31, 32, 33, 34, 35, 36, 37, 38). Similar to what is seen in respectively (Fig. 1 and Table 1) (40, 41). These findings patients with mutations in COL1A1 and COL1A2, in some confirm the importance of collagen 1 metabolism in of the genes, different mutations gave rise to different defining bone mass and bone strength. forms of OI. Furthermore, in literature, other disorders In addition to the genes involved in collagen 1 with decreased BMD and decreased bone strength like biosynthesis, mutations in genes involved in other Bruck syndrome and Cole-Carpenter disease are reported pathways important for human bone formation are to be caused by genes involved in collagen 1 biosynthesis reported to cause OI. For example, mutations in WNT1, (4, 8). These disorders are referred to as OI-like syndromes, a ligand of the WNT signalling pathway and mutations and in case of Bruck syndrome, mutations in two known in Sp7, encoding osterix, an important regulator of OI genes FKBP10 and PLOD2, are reported to be causative mesenchymal stem cell differentiation can cause OI types (Table 1). Patients with Bruck syndrome have in addition III and IV (Table 1) (42, 43, 45, 46). Finally, OI type V to the OI phenotype also contractures of the large joints is caused by mutations in the IFITM5 gene of which the and pterygia (21). Cole-Carpenter is characterised by function is still largely unknown (23). bone deformities that are reminiscent for OI as well as by distinct facial features and ocular proptosis with orbital WNT signalling craniosynostosis (39). The disease was already described in 1987, but recently, whole-exome sequencing (WES) WNT signalling is an important pathway known for resulted in the identification of P4HB and SEC24D, both several decades and involved in a large variety of cellular

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Figure 1 Overview of the most important signalling pathways regulating bone formation identified through the analysis of monogenic bone disorders.

processes. The pathway is activated when a WNT ligand (Table 1) (43). In addition to mutations in WNT1, juvenile binds a Frizzled (Fz) receptor. So far, 19 WNT ligands osteoporosis can also be caused by heterozygous loss-of- and 10 Fz receptors have been described and depending function mutations in LRP5, a co-receptor of the canonical on the ligand, receptor and possible interactions with WNT signalling pathway (57). Moreover, homozygous co-receptors, three different WNT signalling cascades, p mutations in LRP5 are shown to cause osteoporosis one canonical pathway or two non-canonical pathways, pseudoglioma (OPPG), another disorder with a highly can be activated (47). In the beginning of this century, reduced bone mass and increased fracture risk (Table 1) it became clear that especially canonical WNT signalling (50, 58, 59).

European Journal European of Endocrinology is one of the major pathways regulating bone formation Further proof of the importance of LRP5 in the (48, 49, 50, 51). The pathway is activated by the binding regulation of bone formation is found by the identification of a WNT ligand on a receptor complex formed by an Fz of gain of function in patients with autosomal dominantly receptor and an LRP5/6 co-receptor (Fig. 1). Activation of inherited bone disorders marked by an increased bone the pathway results intracellularly in the stabilisation of density such as the high bone mass (HBM) phenotype, β-catenin that can translocate to the nucleus where it can endosteal hyperostosis, Worth disease and osteosclerosis modulate the transcription of target genes. The canonical (Table 1) (51, 60, 61). All identified mutations colocalise WNT signalling pathway can be distinguished from the in the firstβ -propeller domain of the receptor, which is non-canonical pathways based on the use of LRP5/6 as shown to be important for the binding to sclerostin and co-receptor and its intracellular signalling via β-catenin members of the dickoppf (DKK) family, all inhibitors of (Fig. 1) (47, 52). A great amount of evidence for a role the canonical WNT signalling pathway. Due to the HBM of this pathway in the regulation of bone formation mutations, the binding between LRP5 and its antagonists, was found through the identification of mutations in sclerostin and DKK1, is lost which results in increased disorders characterised by an extreme high or low bone activation of the pathway and ultimately in increased mass (Table 1) (48, 49, 50, 51, 53, 54, 55, 56, 57, 58). bone formation (Fig. 1) (62, 63, 64). Sclerostin, encoded In case of low bone mass and strength, we already by the SOST gene, is another important regulator of mentioned that homozygous mutations in WNT1 can bone formation, which is identified through the study cause OI types III and IV (45, 46). In addition, heterozygous of monogenic bone disorders. Deletion of a 52-kb large inactivating mutations in WNT1 can also cause juvenile region, located 35 kb downstream of SOST and harbouring osteoporosis, a condition marked by reduced bone mass an enhancer, is shown to cause Van Buchem disease while and increased fracture risk that presents during childhood loss-of-function mutations in the same gene are found in

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patients with sclerosteosis (48, 49). Van Buchem disease important regulator of bone formation through the and sclerosteosis are both autosomal recessive bone regulation of osteoblast proliferation and differentiation disorders that are both marked by hyperostosis of the skull and matrix mineralisation (47). In addition to the role and tubular bones. Sclerosteosis is the more severe disorder of WNT signalling in the regulation of bone formation, of the two and some sclerosteosis patients deceased as a studies demonstrated that activation of the pathway consequence of the increased intracranial pressure due to influences bone resorption as well by increasing the increased thickness of the skull (65). In addition, mutations expression of osteoprotegerin (OPG) (69). OPG inhibits in SOST were also identified in patients diagnosed with osteoclastogenesis and consequently bone resorption craniodiaphyseal dysplasia, a rare autosomal dominantly through its binding with the RANK ligand (RANKL). In inherited disorder marked by generalised hyperostosis this way, it prevents the binding of RANKL to the RANK and characteristic facial dysmorphisms referred to as receptor and subsequently the activation of the NF-κB lion face, again confirming the importance of sclerostin pathway, which stimulates osteoclastogenesis (Fig. 1) (70). in the regulation of bone formation (Table 1) (66). More recently, we reported that hypomorphic mutations in TGFβ signalling another player of the WNT signalling pathway, namely LRP4, cause sclerosteosis (Table 1) (53, 54). Functional A third important pathway in the regulation of bone studies demonstrated that LRP4 can modulate the WNT homeostasis is the TGFβ signalling pathway (71). In signalling pathway by facilitating the inhibitory actions humans, mutations in some of the players of this pathway of sclerostin (Fig. 1). All identified mutations in LRP4 have shown to cause rare monogenic disorders with colocalise in the third β-propeller domain of the receptor increased bone mass due to increased bone formation and result in decreased binding with sclerostin, which (Table 1). In vivo and in vitro studies demonstrated that the consequently results in increased activity of the WNT TGFβ signalling pathway can affect both bone formation signalling pathway and increased bone formation (53, and resorption and is an important regulator of the bone 54). Another skeletal disorder caused by mutations in a remodelling process (71). modulator of the WNT signalling pathway is Pyle’s disease More than 15 years ago, mutations in TGFβ1 were (OMIM 265900), an autosomal recessive disorder that was p identified to be causative for Camurati-Engelmann first described in 1933 and is marked by long bones with disease (CED), an autosomal dominantly inherited bone wide and expanded trabecular metaphyses, thin cortical disorder marked by generalised sclerosis, hyperostosis of bone and bone fragility. Recently, homozygous truncating the skull base, thickening of the cortex in the long bones, European Journal European of Endocrinology mutations in the gene encoding secreted Frizzled-related chronic bone pain and muscle weakness. The identified protein 4 (sFRP4) were shown to be disease causing mutations are gain-of-function mutations and almost all in patients with Pyle’s disease (67, 68). sFRP4 can bind mutations are located in the latency-associated protein to WNT ligands, and in this way, it can modulate all (LAP) region of TGFβ1 (72, 73, 74). Non-covalent linking different WNT signalling pathways. In mice lacking of the LAP domain to the receptor-binding domains of Sfrp4, the amounts of trabecular bone was increased and active TGFβ1 is important to keep TGFβ1 inactive in the the cortical bone is unusually thin, which resembles the bone matrix. During bone resorption, active TGFβ1 will phenotype seen in patients with Pyle’s disease (68). Finally, be released from the bone matrix (Fig. 1). Due to the extracellular modulators of the WNT signalling pathway CED mutations, the release of active TGFβ1 from the are not alone to carry mutations. Osteopathia striata, an bone matrix is increased. Furthermore, in vitro and in X-linked disorder, is caused by inactivating mutations vivo studies demonstrated that active TGFβ1 is necessary in AMER1, alternatively called WTX, an intracellular for the migration and proliferation of osteoprogenitor inhibitor of the pathway (Fig. 1 and Table 1) (55, 56). The cells to the bone surface after bone resorption. So, due disease is marked by longitudinal striations of long bones, to the CED-causing mutations in TGFβ1, there will be an macrocephaly, cleft palate and hearing loss in females; increased release of active TGFβ1, which results ultimately however, large phenotypic variation is observed due to in abnormal bone remodelling and increased the bone non-random X-inactivation. In males, osteopathia striata turnover (74). is usually mortal in neonatal or foetal stage (56). Osteopoikilosis or alternatively called spotted bone So, identification of above described disease- disease is characterised by the occurrence of small focal causing genes and subsequent in vitro and in vivo studies sclerotic lesions in one or multiple bones (75). When the demonstrated that canonical WNT signalling is an bone phenotype is accompanied by connective tissue nevi,

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it is referred to as Buschke–Ollendorff syndrome (BOS) in PLS3 could explain the osteoporosis phenotype in the (76). Studies have shown that this autosomal dominantly patients. inherited disorder is caused by inactivating mutations in In addition to the above described disorders with the LEMD3 gene. LEMD3 is a nuclear membrane protein a decreased bone mass, there are also monogenic bone that can inhibit the TGFβ signalling pathway by binding disorders with increased bone mass due to defects in to SMAD proteins, the downstream mediators of the osteoblasts that are caused by genes with rather unknown pathway (Fig. 1) (76, 77). In some families, osteopoikilosis function in bone metabolism. Perhaps the most severe and BOS occur together with melorheostosis, a condition disorder is Raine syndrome caused by loss-of-function characterised by asymmetric lesions in the cortex of mutations in FAM20C (81). Raine syndrome is an tubular bones. In addition to the bone, adjacent tissues autosomal recessive disorder that in most cases is fatal in such as skin and muscles are often also affected. This the first weeks of life (82). The disease is characterised by leads to the suggestion that these conditions might be generalised osteosclerosis and typical facial features such allelic; however, several studies were unable to confirm as midface hypoplasia, hypoplastic nose, exophthalmos this (76, 77). and low set ears. In surviving patients, the disease is caused by hypomorphic mutations in FAM20C and in addition to the above described features, surviving Other or unknown function patients often also have amelogenesis imperfecta and mild hypophosphatemia (81, 83, 84). The disease-causing Novel technologies have led to the identification of novel gene, FAM20C, alternatively called dentin matrix protein genes for monogenic bone disorders. Several of these 4, is highly expressed in odontoblasts, ameloblasts, genes are involved in the above described pathways or cementoblasts, osteoblasts and osteocytes (85) and other not yet mentioned pathways. However, the exact encodes for a Golgi casein kinase that is involved in working mechanism or pathway for all identified genes is the phosphorylation of secretory calcium-binding not known. phosphoprotein members such as for example, dentin In the section on osteogenesis imperfecta, we matrix protein 1 (DMP1), osteopontin (OPN), matrix mentioned that not all of the identified genes arep extracellular phosphoglycoprotein (MEPE) and bone involved in collagen 1 biosynthesis. One of these genes sialoprotein (BSP). The contribution of these proteins to is Sp7, encoding for the well-known osteoblast-specific mineralisation is complex; however, it has been reported transcription factor osterix that regulates osteoblast that abnormal phosphorylation of these proteins is European Journal European of Endocrinology differentiation (Table 1). Loss of osterix function results involved in the aberrant mineralisation observed in Raine in reduced osteoblast differentiation and bone formation syndrome (Fig. 1) (86, 87, 88). (44). Another previously mentioned osteogenesis Finally, ANKH and GJA1 are reported to cause imperfecta gene is IFITM5. So far, it is the only gene respectively autosomal dominant and recessive forms of known to cause OI type 5 (Table 1) (23). In vitro studies craniometaphyseal dysplasia (CMD) (Table 1). Individuals have shown that IFITM5 is expressed in the osteoblasts with CMD usually have generalised sclerosis and a during the early mineralisation phase. In vitro data characteristic facial appearance. Frequently, signs of suggest that IFITM5 has a role during mineralisation, but cranial nerve compression such as hearing loss, impaired no serious bone phenotype could be found in an ifitm5- vision or facial paralysis are also reported (89). The AD knockout mouse model (23). Based on these data, more form is more common and milder than the AR recessive research is needed to further elucidate the role of IFITM5 form. It is caused by loss-of-function mutations in the in the regulation of bone formation. ANKH gene, encoding a pyrophosphate transporter (90, A few years ago, mutations in PLS3 were identified 91). ANKH seems to have multiple functions in the bone using exome sequencing in a family with X-linked formation process. On the one hand, it is reported to osteoporosis (Table 1) (78, 79). The role of PLS3 in bone stimulate osteoblastic maturation and differentiation 92, remodelling is still unknown but based on its capacity to whereas on the other hand, it is shown that it is involved bind actin and the expression of PLS3 in the osteocytes, a in the transport of intracellular pyrophosphate to the role in the mechanosensing by the osteocytes is suggested extracellular region. Pyrophosphate is an inhibitor of the (79, 80). As an adaption to mechanical loading, the mineralisation process. Due to the mutations in ANKH, the osteocyte induces increased bone formation for example transport of pyrophosphate out of the cell is reduced and by suppressing SOST expression. In this way, mutations the pyrophosphate-dependent mineralisation inhibition

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is lost, which contributes to the bone overgrowth seen in sizes (14, 97, 98, 99, 100, 101). Such large studies made CMD patients (91). The AR form of CMD is more recently it possible to identify associated variants in a hypothesis- reported to be caused by mutations in the gap junction protein free manner, which results in the identification of novel alpha 1 gene (GJA1) (93), encoding connexin43, which is genes and previously unknown functional pathways. a crucial component of gap junctions and hemichannels Throughout the years, these studies lead to the that are important for the intracellular communication identification of a large number associated (common) in cells. In bone, Cx43 is the most abundantly expressed variants in over 90 genes or 70 loci. For approximately connexin, and in vitro data demonstrated that Cx43 is half of the associated genes additional evidence that for important for the intracellular communication during their involvement in the regulation of bone development osteoblast differentiation (Fig. 1) (94). Knockout of Gja1 or metabolism is available (102). Identification of the role in mice results in delayed skeletal ossification, craniofacial of the other genes in the regulation of bone metabolism abnormalities and osteoblast dysfunction (95). Overall, will contribute to the identification of novel functional studies have shown that connexin43 has a role in the pathways. The largest GWAS published so far is the modulation of bone modelling and bone remodelling GEFOS2 study in 2012 by Estrada et al. (14). This study and that it is involved in the response to hormonal and was able to demonstrate the association of 56 loci with mechanical stimuli by regulating the expression of osteo- BMD, which was an enormous increase compared to the anabolic and catabolic target genes. However, the exact previous study were 20 associated loci were identified. mechanism behind this regulation needs to be further This increase was mainly due to the significant increase elucidated (94). in sample size compared to the first GWAS study. In In addition, some rare genetic autoinflammatory bone addition, the GEFOS2 study also demonstrated 14 of the syndromes are described including Majeed syndrome, 56 loci that are associated with BMD are also associated deficiency of interleukin-1 receptor antagonist (DIRA) and with osteoporotic fracture risk. In order to find the cherubism. They are caused by the activation of the innate connection between the associated loci, pathway analysis immune system leading to an osseous inflammatory was performed on the associated loci, which highlighted process. The disease-causing genes for these conditions the importance of three biological pathways. First, the are respectively LPIN2, Interleukin-1 Receptor Antagonist p RANK–RANKL–OPG pathway, which is important for ILIRN and SH3-binding protein 2 (SH3BP2) (96). the differentiation and activity of osteoclasts (Fig. 1). The second connection was found between important regulators of mesenchymal stem cell differentiation, and European Journal European of Endocrinology Complex bone disorders finally, many associated genes turned out to be involved in the WNT signalling pathway (14). Identification of In the introduction, we already mentioned that the above the WNT signalling pathway and mesenchymal stem cell described monogenic bone disorders occur in a very small differentiation as important regulators of BMD through group of patients. In most individuals, BMD is defined by GWASs again confirms the importance of the regulation a complex interplay between genetic variation in many of bone formation for BMD. Although the GEFOS2 study genes and environmental factors. As BMD is the most was able to demonstrate significant associations with important predictor of osteoporosis, throughout the that many variants, only 5.8% of the genetic impact on years, many studies have been performed to identify these femoral neck BMD could be explained by all variants genetic factors. Although BMD is the most important together (14). The above presented numbers symbolise predictor of osteoporosis, clinically, the occurrence both the strength of GWAS to identify novel associated of osteoporotic fractures is more relevant and only genes and variants as well as its limitation in explaining partially correlates with BMD. Consequently, different the total genetic variation of BMD. The latter implies that genetic factors can contribute to BMD and osteoporotic a lot of information remains unknown, currently referred fracture risk. to as the missing heritability. In order to unravel the genetic factors contributing Common variants to the missing heritability, different approaches are undertaken. One possible strategy that can be used is In the last decade, several genome-wide association increasing the sample size of the study population. studies (GWASs) and meta-analyses of GWASs have been However, it needs to be noted that increasing the performed in populations with ever-increasing sample sample size can also lead to increased heterogeneity of

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the concort, reducing the chances to replicate previous As previously mentioned, RANKL–RANK interaction findings. (16). On the 2016 annual ASBMR meeting, is important for the activation of osteoclastogenesis the GEFOS consortium presented data of a novel effort and bone resorption. Consequently, the reduced bone to explain more of the heritability using the samples mass seen in the presence of the nonsense mutation in from the largest genome-wide genotyped cohort in the LGR4 and in the Lgr4-knockout mouse can not only be world (UK-Biobank). In this cohort, a large-scale GWAS explained by a delay in osteoblast differentiation and of calcaneal eBMD (estimates bone mineral density mineralisation but also by an increased bone resorption based on quantitative ultrasound) was performed. This (105, 106). Investigation in other populations suggested study identified 403 independent associated SNPs from that the variant is specific for the Icelandic population. 376 loci, which together explained around 13% of the So, the role of genetic variation in LGR4 in other genetic variation in eBMD (103). In the future, it will populations than the Icelandic population remains be a challenge to identify all causative SNPs and genes unclear and needs to be further investigated (104). The for these associations. Identification of these genes will second study combined both data from whole genome indisputably result in the identification of new pathways and whole exome sequencing to impute variants that are regulating bone formation. This study provides evidence missing in previous GWAS (107). Using this strategy, the that increasing the sample size of the study population authors identified a low-frequency non-coding variant is a useful strategy to unravel at least a part of the (rs11692564, MAF 1.7%) 53 kb downstream of engrailed missing heritability. homeobox-1 (EN1) that is associated with both BMD

(BMDlumbar spine: β = 0.22) and fracture risk (OR: 0.85) (107). Although, the effect size of this variant is small compared Rare variants to the effect of the variant in LGR4 described previously, it is much bigger than the effect of common variants In another attempt to explain the missing heritability, (14, 107). Furthermore, more recently, the association of the focus shifts to the study of rare variants instead rs11692564 with BMD was replicated in a population of of common variants. The implementation of next- children and adolescents (108). EN1 expression is found in generation sequencing (NGS) technology in GWAS can p cells from osteogenic lineages and is shown to be involved especially be helpful in the identification of rare variants in the WNT signalling pathway by interacting with the as GWAS studies only focused cover common variants. WNT signalling antagonist Dkk1. Studies in self-deleted So far, only a few whole-genome sequencing (WGS) EN1 (sdEN1) conditional mutant mice show a lower European Journal European of Endocrinology association studies focusing on BMD or osteoporotic trabecular and cortical bone mass, which is suggested to be fracture risk have been published. The first study was the result of increased osteoclastic activity driven by the performed by Styrkarsdottir et al. (104) and demonstrated deletion of EN1 in osteogenic cells (107). In addition, in that a rare nonsense variant in the Leucine-Rich Repeat an Icelandic population, an additional variant in the EN1 Containing G Protein-Coupled Receptor 4 (LGR4) gene gene, rs115242848, is shown to be associated with LS and is strongly associated with low BMD among other hip BMD and osteoporotic fracture by a WGS association phenotypes in the Icelandic population with large effect study. Furthermore, rare variants in genes previously

sizes (ORosteoporosis: 3.27 and ORfractures : 3.12) compared to shown to be associated with BMD, namely SOST, AXIN1 previous studies (14, 104). The associated bone and other and COL1A2, are also reported to be associated with phenotypes are similar to phenotype reported in the Lgr4- BMD in the Icelandic population (109, 110). Moreover, knockout mice (104, 105). In literature, it is suggested the identified rare variants inSOST and COL1A2 are that Lgr4 can regulate bone homeostasis through the also associated with fracture risk. Finally, in the same regulation of both bone formation and bone resorption. population, Styrkarsdottir et al. also demonstrated that a Although, LGR4 is reported to be a receptor for R-spondins, rare variant in the PTCH1 gene is associated with BMD and which can modulate WNT signalling activity, in vitro and fracture risk (109). PTCH1, encodes the PTCH1 receptor, in vivo studies in knockout mice demonstrated that Lgr4 which is involved in the hedgehog pathway, a pathway regulates osteoblast differentiation and mineralisation previously shown to be involved in the regulation via another regulatory mechanism namely cAMP-PKA- osteoblastogenesis and chondrocyte differentiation (111). Aft4 signalling (105). In addition, a recent study reported Previously described studies demonstrate that WGS that Lgr4 negatively regulates osteoclast differentiation can be a useful technique for the identification of rare and bone resorption by interacting with RANKL (106). variants associated with BMD. Typically, the effect size of

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these rare variants will be larger compared to the effect addition, in osteoporosis patients, increased methylation of common variants. However, to have enough power to of the SOST promoter and consequently a decreased level identify these rare variants, very large study populations of sclerostin in the serum of the patients was reported are needed. Furthermore, rare variants alone can probably (122). Not only the WNT signalling pathway but also other not explain all the missing heritability. pathways know to be important in the regulation of bone metabolism such as the RANKL–RANK–osteoprotegerin pathway are shown to be modulated by DNA methylation Other genetic variation (123). It is clear that in addition to common and rare In addition to the effect of common and rare variants on variants that are mostly studied, other genetic variation bone mass, the effect of other genetic variation such as copy also contributes to the regulation of bone formation; number variation (CNV), DNA methylation, microRNAs however, more studies are needed to further elucidate and (miRNAs) and long non-coding RNAs can contribute to identify these factors. the variation in bone mass. Recently, research into the effect of other genetic variation on bone mass and on the Therapeutic opportunities development of osteoporosis gained more interest. The association of CNVs with bone mass and As mentioned, osteoporosis is a common disease marked osteoporosis is only studied by a few GWAS. These studies by reduced bone mass and increased fracture risk. At the reported that VSP13B, UGT2B17 and an intergenic region moment, the treatment of osteoporosis is mainly focused within the 6p25.1 locus and 20q13.12 are associated with on reducing bone loss. However, this is not always bone mass, osteoporosis or osteoporotic fractures (112, sufficient to prevent fractures on the long term. Using 113, 114, 115, 116, 117). antiresorptive treatments such as bisphosphonates or In addition to the effect of CNVs on bone mass and teriparatide, the bone remodelling process will be inhibited osteoporosis, studies also focus on the effect of so-called and osteoblasts will not be stimulated to produce new epigenetic changes, miRNAs and DNA methylation, on the bone. During the past years, genetic studies highlighted a variation in bone mass and osteoporosis risk. Epigenetics large amount of genes and pathways that are important for refers to stable and heritable changes in phenotype or gene p the regulation of human bone formation. Throughout the expression attributable to mechanisms other than changes years, studies have shown that these pathways, especially in the underlying DNA sequence. These mechanisms are the Wnt signalling pathway, are promising targets for the dependent on interactions between the environment and treatment of osteoporosis. European Journal European of Endocrinology the genome (4, 118). MiRNAs are small non-coding RNAs So far the most important and best studied target is that are incorporated into the RNA-induced silencing sclerostin. Sclerostin inhibits the WNT signalling pathway complex (RISC) and that can by binding to messenger by binding to LRP5 or LRP6 and loss-of-function mutations RNA (mRNA) modulate the expression of target genes. in the SOST gene, encoding sclerostin, result in increased Studies have shown that most miRNAs are able to bind bone formation in sclerosteosis and Van Buchem disease and modulate several mRNAs, and most mRNAs can be patients (47). Moreover, expression of sclerostin is mainly targeted by several miRNAs. So far, numerous miRNA have limited to osteogenic cells. Based on these findings, been reported to regulate osteogenesis and osteoporosis several companies developed sclerostin antibodies for the risk (119, 120). treatment of osteoporosis. Most advanced are the studies DNA methylation is another epigenetic mechanism of Romosozumab (Amgen and UCB) of which phase III that is studied for its role in the regulation of bone mass. clinical trial results are recently published (124). This study It is a reversible modification of a cytosine residue located compared one-year Romosozumab treatment followed by 5′ to a guanosine residue (CpG). DNA methylation that one-year Denosumab treatment with one-year placebo primarily represses gene expression by either inhibiting or treatment followed by one-year Denosumab treatment facilitating binding between proteins and DNA. The role were started in post-menopausal women. The results of of DNA methylation in the regulation has been shown this study demonstrated that one-year Romosozumab by several studies. For example, it is been shown that treatment resulted in decreased risk of both vertebral differentiation of osteoblasts to osteocytes is accompanied and clinical fractures (124). Although, the results look by decreased methylation of the SOST promoter, which promising, the clinical study and sclerostin antibody facilitates osteocyte-specific expression of SOST (121). In treatment also have some limitations as described by

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S Papapoulos recently (125). The patients with severe of osteoporosis through bone formation; however, disease (T-score <−3.5) are excluded from the study, additional studies will be needed to confirm this. although bone-forming therapies are designed primarily Finally, the increased knowledge on the genetic cause for these patients. Furthermore, phase II and III clinical of monogenic and complex bone disorders leads to novel trials demonstrated that continuous stimulation of bone opportunities for the treatment, prevention and diagnosis formation through the inhibition of sclerostin is unlikely of skeletal disorders. In case of monogenic disorders, after one year (124, 126). In addition, phase III clinical the implementation of next-generation sequencing in trials demonstrated that the effect of Romosozumab on diagnostics will help clinicians with the diagnosis of non-vertebral fractures is influenced by the geographical the patients. With regard to polygenic disorders, the region. The study demonstrated that patients recruited implementation of genetic testing is more complex. As from Latin America have a lower incidence of non-vertebral discussed in the section on complex bone disorders, many fractures, and only when this ethnic group is excluded variants with small effect sizes contribute to the variation from the analysis, significant results could be observed for in bone mass and fracture risk and consequently also to non-vertebral fractures. Finally, in Romosozumab-treated the risk of osteoporosis. Although already many variants patients, injection site reactions were more common have been identified through the years, they only explain compared to the placebo group. Furthermore, in this a small fraction of the variation in bone mass and only group, one atypical femoral fracture and two cases of have a small predictive value. osteonecrosis of the jaw were reported (124). Although these side effects are only reported in a very small number Conclusion of patients and there were some confounding factors that probably contributed to the event in these patients, these The bone remodelling process is a complex interplay findings raise some questions that need to be elucidated between bone resorption and bone formation. Throughout in the future (125). the years, genetic studies largely contributed to the current In addition to sclerostin another modulator of the knowledge on pathways regulating bone remodelling WNT signalling pathway, DKK1, is currently studied as and offered several possible therapeutic targets for the an interesting therapeutic target (Fig. 1). DKK1 is one p treatment of osteoporosis and other bone disorders. As of the associated genes from the GWAS. Furthermore, increasing bone formation is currently seen as the most heterozygous deletion of Dkk1 in mice results in an promising strategy in the therapy of osteoporosis, we increased bone mass and in mice and in patients focused in this review on genetic evidence for pathways European Journal European of Endocrinology lacking sclerostin, DKK1 expression is upregulated or genes involved in this process. Currently, the WNT (127, 128, 129). Based on these data and its role in the signalling pathway is extensively studied as a possible WNT signalling pathway, DKK1 was suggested to be an therapeutic target, but identification of novel genes or interesting therapeutic target. DKK1 antibodies (BHQ880, pathways in the future will increase the insights in the RH2-18) are studied in animal models for osteoporosis, regulation of bone remodelling and will definitively offer multiple myeloma and rheumatoid arthritis (130, 131, novel therapeutic targets. 132, 133). Treatment of multiple myeloma with BHQ880 seems most promising and clinical trials are currently Declaration of interest ongoing (134). Finally, another interesting target for The authors declare that there is no conflict of interest that could be bone-forming therapy is LRP4. As previously mentioned, perceived as prejudicing the impartiality in this review. LRP4 is, as a binding partner of sclerostin, also involved in the regulation of canonical WNT signalling activity Funding and bone formation (47). Although LRP4 is more widely This research did not receive any specific grant from any funding agency in expressed than sclerostin, we and others demonstrated the public, commercial or not-for-profit sector. that the central cavity of the third β-propeller domain of the receptor is important for its role in bone formation Acknowledgements (53, 54). Furthermore, deletion of Lrp4 only in osteoblasts The research was supported by grants of the Fonds voor Wetenschappelijk or osteocytes resulted in mice in increased bone mass Onderzoek Vlaanderen (FWO grant G019712N and G031915N) and the due to increased bone formation and decreased bone European Community’s Seventh Framework Programme (FP7/2007–2013) under grant agreement No. 602300 (SYBIL). E B holds a postdoctoral grant resorption (128). So, based on these findings, it seems that with the Fonds voor Wetenschappelijk Onderzoek Vlaanderen (FWO LRP4 can be another interesting target for the treatment personal grant 12A3814N).

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Received 2 December 2016 Revised version received 15 March 2017 Accepted 5 April 2017

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