Novel actions of sclerostin on bone

Abstract

The discovery that two rare autosomal recessive high bone mass conditions were caused by the loss of sclerostin expression prompted studies into its role in bone homeostasis. In this article, we aim to bring together the wealth of information relating to sclerostin in bone though discussion of rare human disorders in which sclerostin is reduced or absent, sclerostin manipulation via genetic approaches and treatment with antibodies that neutralise sclerostin in animal models and in human. Together, these findings demonstrate the importance of sclerostin as a regulator of bone homeostasis and provide valuable insights into its biological mechanism of action. We summarise the current state of knowledge in the field, including the current understanding of the direct effects of sclerostin on the canonical WNT signalling pathway and the actions of sclerostin as an inhibitor of bone formation. We review the effects of sclerostin, and its inhibition, on bone at the cellular and tissue level and discuss new findings that suggest that sclerostin may also regulate adipose tissue. Finally, we highlight areas in which future research is expected to yield additional insights into the biology of sclerostin.

Current advances in regulation of bone homeostasis

“…Canonical WNT/β‐catenin signalling is critical to regulate bone‐mass homeostasis 75,76 and occurs in an autocrine or paracrine fashion 77 . Canonical WNT signalling is triggered by binding of extracellular WNT ligand to the low‐density lipoprotein receptor‐related protein 5/6 (LRP5/6), the transmembrane proteins, established as WNT co‐receptors and a frizzled (FZD) family cell‐surface receptor to promote formation of a ternary complex, leading to phosphorylation of the cytoplasmic domain of LRP5/6 (called activated ‘WNT on’ state) 77 . The intracellular abundance and location of β‐catenin provides a central switch in the canonical WNT signalling pathway.…”

“…The LRP5/6‐WNT‐FZD ternary complex leads to translocate the destruction complex to the cell membrane, phosphorylates the intracellular region of LRP5/6, recruits AXIN protein which disrupts destruction complex activity and allows free β‐catenin to accumulate in the cytoplasm. Non‐phosphorylated β‐catenin translocates from the cytoplasm to the nucleus to regulate gene expression 77 …”

Scl-Ab reverts pro-osteoclastogenic signaling and resorption in estrogen deficient osteocytes

“…The Wnt antagonist sclerostin (encoded by the SOST gene), produced by mature osteocytes, binds to LRP5/6 Wnt co-receptors, negatively regulates osteoblast proliferation and differentiation via inhibition of the Wnt/β-catenin signalling pathway, and also promotes osteocyte and osteoblast apoptosis [26].…”

Sclerostin antibodies as novel anabolic therapy for osteoporosis

“…Открытие двух аутосомно-рецессивных заболеваний с высокой плотностью костной ткани, связанных с потерей экспрессии склеростина, вызвало интерес к роли этого белка в костном метаболизме. Склеростеоз и болезнь ван Бухема -два схожих заболевания, впервые описанные в 1950-х гг., развиваются вследствие мутаций, так или иначе затрагивающих ген SOST, приводя к потере кодируемого им белка -склеростина [1]. У пациентов со склеростеозом и болезнью ван Бухема наблюдается генерализованный склероз костей, что приводит к повышению минеральной плотности костной ткани (МПК) во всех костях скелета.…”

“…Основные эффекты действия склеростина в костной ткани суммированы на рисунке 1. С учетом механизма действия склеростина, в последующем были разработаны моноклональные антитела, которые связываются со склеростином и препятствуют его взаимодействию с LRP5/LRP6, что, в свою очередь, приводит к усилению костеобразования [1]. В доклинических и клинических исследованиях были исследованы несколько различных антител к склеростину: ромосозумаб (Amgen/UCB), блосозумаб (Eli Lilly) и BPS804 (Novartis).…”