Connective Tissue Research ISSN: 0300-8207 (Print) 1607-8438 (Online) Journal homepage: https://www.tandfonline.com/loi/icts20 Advances in the pathogenesis and possible treatments for multiple hereditary exostoses from the 2016 international MHE conference Anne Q. Phan, Maurizio Pacifici & Jeffrey D. Esko To cite this article: Anne Q. Phan, Maurizio Pacifici & Jeffrey D. Esko (2018) Advances in the pathogenesis and possible treatments for multiple hereditary exostoses from the 2016 international MHE conference, Connective Tissue Research, 59:1, 85-98, DOI: 10.1080/03008207.2017.1394295 To link to this article: https://doi.org/10.1080/03008207.2017.1394295 Published online: 03 Nov 2017. Submit your article to this journal Article views: 323 View related articles View Crossmark data Citing articles: 1 View citing articles Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=icts20 CONNECTIVE TISSUE RESEARCH 2018, VOL. 59, NO. 1, 85–98 https://doi.org/10.1080/03008207.2017.1394295 PROCEEDINGS Advances in the pathogenesis and possible treatments for multiple hereditary exostoses from the 2016 international MHE conference Anne Q. Phana, Maurizio Pacificib, and Jeffrey D. Eskoa aDepartment of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA, USA; bTranslational Research Program in Pediatric Orthopaedics, Division of Orthopaedic Surgery, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA ABSTRACT KEYWORDS Multiple hereditary exostoses (MHE) is an autosomal dominant disorder that affects about 1 in 50,000 Multiple hereditary children worldwide. MHE, also known as hereditary multiple exostoses (HME) or multiple osteochon- exostoses; multiple dromas (MO), is characterized by cartilage-capped outgrowths called osteochondromas that develop osteochondromas; EXT1; adjacent to the growth plates of skeletal elements in young patients. These benign tumors can affect EXT2; heparan sulfate; growth plate; skeletal growth plate function, leading to skeletal growth retardation, or deformations, and can encroach on development nerves, tendons, muscles, and other surrounding tissues and cause motion impairment, chronic pain, and early onset osteoarthritis. In about 2–5% of patients, the osteochondromas can become malig- nant and life threatening. Current treatments consist of surgical removal of the most symptomatic tumors and correction of the major skeletal defects, but physical difficulties and chronic pain usually continue and patients may undergo multiple surgeries throughout life. Thus, there is an urgent need to find new treatments to prevent or reverse osteochondroma formation. The 2016 International MHE Research Conference was convened to provide a forum for the presentation of the most up-to-date and advanced clinical and basic science data and insights in MHE and related fields; to stimulate the forging of new perspectives, collaborations, and venues of research; and to publicize key scientific findings within the biomedical research community and share insights and relevant information with MHE patients and their families. This report provides a description, review, and assessment of all the exciting and promising studies presented at the Conference and delineates a general roadmap for future MHE research targets and goals. Introduction threatening, because of their common resistance to chemo- or radiation therapy (5,6). No new osteochondro- Multiple hereditary exostoses (MHE) is a rare, pediatric, mas form after the end of puberty when all the growth and autosomal dominant musculoskeletal disorder that plates close and the skeleton reaches maturity. affects about 1 in 50,000 children worldwide (1,2). Current treatments for MHE mainly consist of surgical MHE, also known as Hereditary Multiple Exostoses removal of the most symptomatic tumors and correction (HME) or Multiple Osteochondromas (MO), is amongst of major skeletal defects such as deformations, limb the most common disorders within the NIH Office of length discrepancies, and joint ankylosis, and patients Rare Diseases classification and one of the most frequent often undergo more than 40–50 surgeries by age 18 (7). causes of bone tumors. As its name implies, MHE is However, because the osteochondromas are so numerous characterized by osteochondromas, benign cartilage- and often difficult to reach and resect, many are left in capped outgrowths with a bony stem developing adjacent place; consequently, a considerable number of patients to the growth plates of long bones, vertebrae, ribs, and struggle with pain and physical difficulties through life pelvis in juvenile patients (3,4). The tumors can affect the (8,9). As recent studies indicate, patients can suffer from normal functioning of growth plates, leading to growth additional non-skeletal health problems that include retardation and skeletal deformations. They can also social and learning difficulties, sleep disorders, and neu- impinge on nerves, tendons, blood vessels, muscles, and ropathies (10–12). MHE may also involve alterations in other surrounding tissues, causing motion impairment, postprandial lipid clearance and pancreatic beta-cell chronic pain, and even early onset osteoarthritis. In reserve due to smaller pancreas volume (13,14), making about 2–5% of patients, the osteochondromas transform MHE a syndrome rather than a pure skeletal condition. into malignant chondrosarcoma that can be life CONTACT Jeffrey D. Esko [email protected] Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093- 0687, USA. © 2017 Taylor & Francis 86 A. Q. PHAN ET AL. MHE is linked to heterozygous loss-of-function muta- perichondrium (35–37). Other studies showed that chon- tions in EXT1 (8q24.1) or EXT2 (11p11-12) (15–17)that drocytes in zebrafish mutants lacking dackel (correspond- encode Golgi-associated glycosyltransferases responsible ing to mammalian Ext2) grew aberrantly and lost polarity, for the biosynthesis of heparan sulfate (HS) (18). HS is a invading surrounding tissues, thus mimicking traits of complex glycosaminoglycan polymerized from alternat- MHE chondrocytes (38). Human MHE growth plate ing N-acetylglucosamine and glucuronic acid residues, chondrocytes display disorganized primary cilia and loss and both EXT1 (the enzyme) and EXT2 (the chaperone- of cellular polarity, suggesting that the cells were unable to like and non-enzymatically active partner of EXT1) are perceive cilia-mediated signals and maintain cell align- needed for its synthesis (19,20). The HS chains are poly- ment and location, thus contributing to osteochondromas merized and covalently linked to small subset of HS-rich (39). Huegel et al. showed that Ext1 and HS regulate proteoglycans (HSPGs) and undergo extensive, concur- perichondrial phenotype and border function in develop- rent chain modifications including sulfation at various ing long bones and that the loss of Ext1 in perichondrial positions and glucuronic acid epimerization, resulting in progenitor cells led to osteochondroma formation (40). chains with a high degree of structural complexity and Boundary defects may be reinforced by changes in biological specificity (21,22). The HSPG family includes microRNAs demonstrated in MHE chondrocytes (41). cell surface proteoglycans (4 syndecans, 6 glypicans, Studies also indicated that the HS deficiency in MHE CD44V3, betaglycan, and CD47), pericellular/extracellu- cartilage and perichondrium could be exacerbated by lar matrix proteoglycans (perlecan, agrin, and Type XVIII abnormally high expression of heparanase (42,43). In collagen), and serglycin (21,23,24). The HSPGs are summary, there has been significant progress in uncover- expressed in a tissue-specific manner and have a number ing aspects of the genetics and cellular pathogenesis of of important developmental and physiologic functions MHE using both animal models and human MHE speci- (24). One of their main roles is to interact with growth mens. However, much remains to be understood factors, morphogens, and receptors, all characterized by mechanistically, and relatively little has been achieved so possessing a specific HS-binding domain (25,26). The far toward the development of treatments to prevent HSPGs regulate protein availability, distribution, turn- osteochondroma formation and/or growth (44). over, and signaling, thus affecting cell adhesion and As pointed out above, MHE is not simply a skeletal migration, cell–cell interactions and communication, disease, but encompasses non-skeletal pathologies (9). cell differentiation and morphogenesis, and lipoprotein Unlike skeletal abnormalities, these additional patholo- metabolism and proteases involved in hemostasis and gies occur with varying frequency and have been dis- development (21,23,24). The EXT deficiency in MHE counted or unappreciated in the past. However, recent results in partial truncation of the HS chains, which human and mouse studies have provided evidence that leads to lower levels of HS in multiple tissues and plasma HS deficiency can in fact cause physiological defects in (27–29), potentially explaining the impact of the muta- kidney organization and podocyte structure (13), neuro- tions on multiple organ systems. nal cell signaling and mouse behavior (45,46), lipid The haploinsufficiency in EXT1 or EXT2 in MHE metabolism (47,48), intestinal epithelial barrier function patients can in itself cause certain pathologies