First missense mutation in the SOST gene causing sclerosteosis by loss of sclerostin function

Piters, Elke; Culha, Cavit; Moester, M. J. C.; Bezooijen, R. Van; Adriaensen, Dirk; Mueller, Thomas D.; Weidauer, Stella E.; Jennes, Karen; Freitas, Fenna de; Löwik, Clemens W.G.M.; Timmermans, Jean‐Pierre; Hul, Wim Van; Papapoulos, Socrates E.

doi:10.1002/humu.21274

Cited by 53 publications

(25 citation statements)

References 20 publications

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“…SOST is involved in bone homeostasis, in particular and acts as a direct extracellular antagonist of canonical Wnt signaling by binding to lipoprotein receptor-related protein-5/6 (LRP5/6) (Krause et al 2010;Semënov et al 2005). Loss of function of SOST causes high bone mineral density in humans (Piters et al 2010;Bhadada et al 2013), while SOST overexpression in transgenic mice leads to reduced bone formation and osteopenia (Winkler et al 2003). SOST can regulate mechanical and inflammatory bone remodeling (Robling et al 2008;Heiland et al 2010).…”

Section: Discussionmentioning

confidence: 99%

Comparison of tissue transglutaminase 2 and bone biological markers osteocalcin, osteopontin and sclerostin expression in human osteoporosis and osteoarthritis

et al. 2016

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Osteoporosis (OP) and osteoarthritis (OA) are the most common joint diseases, with a high incidence in the elderly population. OP is characterized by trabecular bone remodeling and reabsorption, whereas articular cartilage and subchondral bone remodeling are major features of OA. Although classically considered as independent or even conflicting processes, clinical coexistence of OP and OA was recently described. Transglutaminase 2 (TG2) expression is considered a biomarker of OA, but its role in osteoporotic bone remodeling is still uncertain. We investigated TG2 and bone biological markers (Osteocalcin, Osteopontin, and Sclerostin) in osteoporotic and osteoarthritic osteocartilagineous tissue (n = 54) and human chondrocyte cultures in vitro by immunohistochemistry, immunofluorescence and RT-PCR. Histomorphometric evaluation of bone trabecular remodeling was also performed. In cartilage, TG2 expression was faint in control and OP and significantly less than in OA and OP + OA chondrocytes; the opposite was found for Osteocalcin, whereas Osteopontin and Sclerostin expression was similar. In the subchondral trabecular bone, osteocytes/osteoblasts TG2 expression was slight and similar comparing control, OP, OA, and OP + OA group, whereas Osteocalcin and Osteopontin expression was lower in OP compared to control, OA and OP + OA. Increased TG2 and reduced Osteocalcin expression were maintained in human osteoarthritic chondrocytes in vitro. Histomorphometric analysis confirmed reduced trabecular bone mass in OP and OP + OA compared with OA patients. TG2 represented a suitable biomarker of osteoarthritic chondrocyte activation, whereas osteocalcin and osteopontin characterized osteoporotic osteocyte/osteoblast changes; differences were lost in OP + OA patients, suggesting careful consideration when coexistence of the two diseases occurs.

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Section: Discussionmentioning

confidence: 99%

Comparison of tissue transglutaminase 2 and bone biological markers osteocalcin, osteopontin and sclerostin expression in human osteoporosis and osteoarthritis

et al. 2016

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confidence: 99%

“…19 Mutations in SOST gene causing sclerostin loss of function are associated with a clinical syndrome of progressive bone thickening known as sclerosteosis. 20,21 Efficacy of a monoclonal sclerostin neutralizing antibody (Scl-Ab) to increase bone mass and strength and in promoting fracture healing has been demonstrated in several animal models including female osteoporotic rats, aged male rats, and gonad-intact non-human primates. 5,6,22 We previously used a critical sized 6 mm defect in the Lewis rat femur to evaluate the effects of Scl-Ab treatment on critical sized bone defect healing and found that it led to increased bone formation, but complete healing of the femoral defects occurred in only a small subset of rats.…”

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confidence: 99%

Evaluation of the effects of systemic treatment with a sclerostin neutralizing antibody on bone repair in a rat femoral defect model

Alaee

Virk

Tang

et al. 2013

Journal Orthopaedic Research

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Systemic administration of a sclerostin neutralizing antibody (Scl-Ab) has been shown to enhance fracture callus density and strength in several animal models. In order to further evaluate the potential of Scl-Ab to improve healing in a bone defect model, we evaluated Scl-Ab in a 3 mm femoral defect in young male outbred rats. Scl-Ab was given either continuously for 6 or 12 weeks after surgery or with 2 weeks of delay for 10 weeks. Bone formation was assessed by radiographs, m-CT, and histology. Complete bony union was achieved in only a few defects after 12 weeks of healing (Scl-Ab treated 5/30, vehicle treated 1/15). m-CT evaluation demonstrated a significant increase in the BV/TV in the defect in the delayed treatment group (65%, p < 0.05), but a non-significant increase in the continuous group (35%, p ¼ 0.11) compared to control. However, both regimens induced an anabolic response in the bone proximal and distal to the defect and in the un-operated femurs. We demonstrate that treatment with Scl-Ab can enhance bone repair in a bone defect and in the surrounding host bone, but lacks the osteoinductive activity to heal it. This agent seems to be most effective in bone repair scenarios where there is cortical integrity. The Wnt/b-catenin signaling pathway is known to be a key regulator of bone formation and its role in fracture healing has been established in several studies. 1-3This pathway is a target for developing strategies to promote bone fracture healing. 4 In pre-clinical studies activation of the Wnt pathway either by inhibiting Wnt inhibitors such as sclerostin [5][6][7] or DKK1 8 or more recently by liposomal delivery of Wnt3a 9 has been shown to enhance bone repair. Fracture non-union may occur in as many as 10% of all fractures. 10Treatment of non-unions may require multiple surgeries and prolonged hospital stays which leads to increased cost of treatment.11 Autologous bone graft remains the gold standard for management of nonunions, but there are disadvantages including donor site morbidity and limited availability. 12,13 BMPs are osteoinductive proteins that are FDA approved to treat open tibial shaft fractures 14,15 and to facilitate lumbar spine fusions. 16 The success of BMPs in humans has been variable and it is an expensive treatment associated with side effects such as local soft tissue edema 17 and ectopic bone formation.18 Therefore there is interest in identifying systemic agents that can enhance the healing of fractures.Sclerostin, a product of SOST gene, is primarily secreted by osteocytes and inhibits the Wnt pathway by interacting with the LRP5/6. 19 Mutations in SOST gene causing sclerostin loss of function are associated with a clinical syndrome of progressive bone thickening known as sclerosteosis. 20,21 Efficacy of a monoclonal sclerostin neutralizing antibody (Scl-Ab) to increase bone mass and strength and in promoting fracture healing has been demonstrated in several animal models including female osteoporotic rats, aged male rats, and gonad-intact non-human primates....

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“…Recent advances in molecular genetics have revealed that both of them are caused by functional mutations in the SOST gene, which is localized in the 17q12-21 chromosomal region and codes for sclerostin, a glycoprotein that is solely expressed by osteocytes. [3][4][5][6] Sclerostin acts as a negative regulator of bone formation, through inhibition of the Wnt signaling pathway, which is of critical importance for the development and function of osteoblasts. 7 Undetectable or very low levels of sclerostin in these patients result in excessive bone growth and increased bone strength 8 ( Figure 1).…”

Section: Meostasismentioning

confidence: 99%

“…9 It is caused by 6 different types of lossof-function mutations of the SOST gene, resulting in reduced production of sclerostin, and is inherited in an autosomal-recessive mode. 6 All patients are homozygous for these mutations and the complete absence of sclerostin results in overgrowth of skull bones, mandible, ribs, clavicles, long bones and pelvis. Patients are usually tall and have a characteristic face because of the facial deformities of bossing of the forehead and enlargement of the mandible.…”

Section: Sclerosteosismentioning

confidence: 99%

The sclerostin story: From human genetics to the development of novel anabolic treatment for osteoporosis

Yavropoulou

Xygonakis

Lolou

et al. 2014

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Sclerosteosis and Van Buchem disease are two rare bone sclerosing disorders characterized by increased bone mineral density, tall stature and entrapment of cranial nerves due to overgrowth of a highly dense bone. Recent advances in human genetics have revealed the genetic background of these disorders by cloning the SOST gene, which is localized on chromosome region 17q12-q21 and codes for sclerostin. Sclerostin is a protein produced almost exclusively from osteocytes inhibiting bone formation by both osteoblasts and osteocytes. At the molecular level, sclerostin inhibits the Wnt signaling pathway, which plays a critical role in osteoblast development and function. Induced sclerostin deficiency in mice reproduces the bone sclerosing human diseases, while sclerostin excess leads to bone loss and reduced bone strength. The extracellular nature of sclerostin has rendered it a promising target for the development of novel anti-osteoporotic treatment. Otherwise healthy carriers of the SOST mutation present with increased bone mass and low levels of sclerostin in serum in contrast to patients with sclerosteosis, who exhibit undetectable levels, thus pointing to the possibility of titration of sclerostin levels in the circulation. Based on these unique characteristics, human anti-sclerostin antibodies have been developed and tested in ovariectomized rats and monkeys, demonstrating very promising results in bone formation. Clinical phase II and III trials are currently underway thereby translating human genetics to drug development.

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First missense mutation in the SOST gene causing sclerosteosis by loss of sclerostin function

Cited by 53 publications

References 20 publications

Comparison of tissue transglutaminase 2 and bone biological markers osteocalcin, osteopontin and sclerostin expression in human osteoporosis and osteoarthritis

Comparison of tissue transglutaminase 2 and bone biological markers osteocalcin, osteopontin and sclerostin expression in human osteoporosis and osteoarthritis

Evaluation of the effects of systemic treatment with a sclerostin neutralizing antibody on bone repair in a rat femoral defect model

The sclerostin story: From human genetics to the development of novel anabolic treatment for osteoporosis

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