The controversial molecular mechanisms of sclerostin and relevance to bone maintenance

Michael Junior

Introduction. Sclerostin, a glycoprotein with a high affinity for bone that is encoded by the SOST gene, has been shown to have inhibitory effects on bone formation through various proposed mechanisms but most commonly accepted via inhibition of the Wnt signaling pathway (1-4).   In osteoporosis, a disorder of bone turnover characterized by increased bone resorption and decreased bone formation, increased serum sclerostin levels are found (1,5).  Studies have commonly shown that sclerostin inhibits the Wnt signaling pathway by binding to low-density lipoprotein receptor-related protein 5 & 6 (Lrp5/6) (2,6,7). Other studies have found that sclerostin inhibits osteoblastogenesis by activating platelet-derived growth factor receptor (PDGFR) platelet-derived growth factor promotes osteoclastogenesis (4,8). Current sclerostin targeted therapy for osteoporosis implements anti-sclerostin antibodies as a mechanism for preventing sclerostin-mediated inhibition of osteoblastogenesis, but knowledge of the various mechanisms of sclerostin action can have implications on future treatment (6,9). Methods.  RAW264.7 and bone marrow-derived macrophages (BMM) were cultured with recombinant murine PDGF-BB in the presence or absence of PDGFR-beta inhibitor (AG-1295) or Janus kinase 2 inhibitor (AG-490) and tartrate-resistant acid phosphatase (TRAP) staining was used to confirm osteoclast formation (8). Mesenchymal stem cell and osteoclastic precursor cell cultures were analyzed by Western blot analysis in the presence of sclerostin.  Cultures then underwent alkaline phosphatase activity assays (ALP) with PDGFR inhibition (4).  Results.  Osteoclastogenesis was significantly increased by increased PDGF concentration in the presence of RANKL (8).  Sclerostin activated PDGFR similar to PDGF and induced tyrosine phosphorylation of protein kinase C, Akt, and ERK1/2.  ALP showed that inhibition of PDGFR reversed the sclerostin-induced inhibition of osteoclastogenesis (4).  Conclusions.  Studies have found that PDGF-induced activation of PDGFR activates osteoclastogenesis while direct or indirect sclerostin-induced activation of PDGFR inhibits osteoblastogenesis. Though it is commonly accepted that sclerostin inhibits osteoblastogenesis via Lrp5/6-mediated inhibition of Wnt signaling, the data suggest that sclerostin also activates PDGFR and its downstream products subsequently inhibiting osteoblastogenesis. Further studies implementing both mechanisms of sclerostin action on bone turnover could prove to be a potent therapeutic for bone regulation disorders such as osteoporosis.

 

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