Sclerostin (SOST)

model of molecule

  • Sclerosteosis
  • Van Buchen's Disease
  • SOST and wnt
  • Osteocytes and mechanotransduction
  • Animal studies that decrease sclerostin
  • Human studies of sclerostin antibodies
  • The SOST gene is located at 17q12-21, and codes for the protein sclerostin. Sclerostin is made primarily by osteocytes, and it inhibits bone formation and enhances apoptosis of osteoblasts. Patients with mutations in the SOST gene have very high bone density. SOST binds to LRP5 and inhibits the Wnt-signalling pathway. It is also a mild BMP antagonist.

    Weidauer. Biochemical and Biophysical Res Comm. 2009;380:160


    Sclerosteosis

    Sclerosteosis is a serious, autosomal recessive disease with thick bones, entrapment of cranial nerves leading to deafness and facial nerve palsy, increased intracranial pressure, and frequently syndactyly. Patients are tall and heavy but not obese. Most patients are from South Africa and are homozygotic for a specific mutation in the SOST gene, which is mapped to 17q12-21.

    photo of patientxray of hands This figure from the review by Hamersma shows a woman with facial nerve palsy and thick, square mandible. The hand xrays demonstrate the thickened bones of the hands. from Hamersma H et al, 2003, The natural history of sclerosteosis. Clin Genet 63:192-7 used with permission.

    The authors note that none of their 63 patients have ever had a fractured bone. Also, the obligatory heterozygous gene carriers are resistant to fractures. The patients do not have degenerative osteoarthropathy.

    Another report of two siblings who had several features of sclerosteosis showed a different mutation in the SOST gene. They also had thick bones, deafness, facial palsy, but not syndactyly. photo of patientsskull
    from Balemans W, et al. 2005. A generalized skeletal hyperostosis in two siblings caused by a novel mutation in the SOST gene. Bone 36:943-7. Used with permission


    Van Buchem's Disease


    This disease is very similar to sclerosteosis, but without the hand deformities. The mutations are located in a region downstream from the SOST gene. An autosomal dominant disease which is similar is caused by mutation in LRP-5. Beighton P, Barnard A, Hamersma H, van der Wouden A. The syndromic status of sclerosteosis and van Buchem disease. Clin Genet. 1984;25(2):175-81.. Used with permission


    SOST and Wnt

    diagram

    SOST is a homolog of WISE, which binds to LRP-6. SOST binds to LRP-5 which is a co-receptor in the Wnt-signalling pathway. Thus, SOST inhibits Wnt-signalling, similar to Dkk inhibition.


    SOST in osteocytes and mechanotransduction

    photomicrograph SOST is expressed mainly in osteocytes. These cells form a network which senses mechanical strain. Osteocytes can alter the secretion of sclerostin to regulate bone formation.
     
    Osteocytes in culture showing extensive network of flattened cells. from: A van der Plas and PJ ijweide, Isolation and Purification of osteocytes. J Bone Mineral Res 1992;7:389-396. With permission from the American Society for Bone and Mineral Research.

    diagram of mouse experiment

     
    This diagram shows the design of an experiment in which the mouse ulna was either loaded or unloaded to see what happened to the osteocytes in the bone.

    These sections show the ulna in the control mice (top) and the same area in the mice whose were loaded (lower). The H&E stains show that the osteocytes are viable. The close-up shows sclerostin staining, which is almost absent in the loaded arm.

    Robling AG, Niziolek PJ, Baldridge et al. Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/Sclerostin. J Biol Chem 2008;283:5866. Used with permission. photomicrographs of arm


    Animal studies that decrease sclerostin

    drawing of mouse
    xrays of mice
    Mice with SOST knock-out had lower sclerostin levels and higher bone density as shown in these xrays.
     
    Li X. Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J Bone Min Res 2008:23:860

    Treating rats with antibodies against sclerostin results in increased bone, shown in the xrays below, and the quality of the bone is good, with a lamellar pattern and clear tetracycline labels.

    xrays
    photomicrograph of lamellar bone
    Li X Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. J Bone Min Res 2009;24:578


    Human studies of antibodies against sclerostin

    There are two anti-sclerostin antibodies that have been studied in humans. Here's what their names mean:
    ROM, BL = unique prefix assigned to the new drug
    OS = works on the bone
    OZU = humanized
    MAB = monoclonal antibody

    So we have ROMOSOZUMAB and BLOSOZUMAB

    The first pilot study was reported by Padhi. They treated 72 healthy subjects with a single injection of a placebo or the antibody, and saw dose-related increases in the bone density, increases in the bone formation rates, and decreases in the bone resorption rates.

    Similar benefits from initial studies of blosozumab were reported by McColm.

    A new study was done in 419 postmenopausal women with low bone density. They were randomized to placebo, various doses of romosozumab, or alendronate or teriparatide for a year. The bone density at the spine increased by 11.3% with the highest dose that they studied. The markers of bone formation increased transiently and the markers of bone resorption were sustained for the year. No serious side effects were reported.

    graph of study
    McClung MR Romosozumab in Postmenopausal Women with Low Bone Mineral Density. New Engl J Med 2014;370;412. Used with permission.

    logo Feb 2016 there was a press release that a phase 3 study, lasting for a year, showed fracture reduction. There weren't many details in this press release, but it sounded like side effects were minimal.

    Updated 3/5/16