6 results for Aati, O

  • The skeletal effects of the tyrosine kinase inhibitor nilotinib

    O'Sullivan, Susannah; Lin, Jian; Watson, M; Callon, K; Tong, PC; Naot, Dorit; Horne, Anne; Aati, O; Porteous, F; Gamble, G; Cornish, Jillian; Browett, Peter; Grey, Andrew (2011-09)

    Conference poster
    The University of Auckland Library

    View record details
  • The skeletal effects of the tyrosine kinase inhibitor nilotinib.

    O'Sullivan, S; Lin, JM; Watson, M; Callon, K; Tong, PC; Naot, D; Horne, A; Aati, O; Porteous, F; Gamble, G; Cornish, J; Browett, Peter; Grey, A (2011)

    Journal article
    The University of Auckland Library

    Nilotinib is a tyrosine kinase inhibitor (TKI) developed to manage imatinib-resistance in patients with chronic myeloid leukemia (CML). It inhibits similar molecular targets to imatinib, but is a signi???cantly more potent inhibitor of Bcr-Abl. Nilotinib exhibits off-target effects in other tissues, and of relevance to bone metabolism, hypophosphataemia has been reported in up to 30% of patients receiving nilotinib. We have assessed the effects of nilotinib on bone cells in vitro and on bone metabolism in patients receiving nilotinib for treatment of CML. We ???rstly investigated the effects of nilotinib on proliferating and differentiating osteoblastic cells, and on osteoclastogenesis in murine bone marrow cultures and RAW264.7 cells. Nilotinib potently inhibited osteoblast proliferation (0.01???1 uM), through inhibition of the platelet-derived growth factor (PDGFR). There was a biphasic effect on osteoblast differentiation such that it was reduced by lower concentrations of nilotinib (0.1???0.5 uM), with no effect at higher concentrations (1 uM). Nilotinib also potently inhibited osteoclastogenesis, predominantly by stromal-cell dependent mechanisms. Thus, nilotinib decreased osteoclast development in murine bone marrow cultures, but did not affect osteoclastogenesis in RAW264.7 cells. Nilotinib treatment of osteoblastic cells increased expression and secretion of OPG and decreased expression of RANKL. In 10 patients receiving nilotinib, levels of bone turnover markers were in the low-normal range, despite secondary hyperparathyroidism, ???ndings that are similar to those in patients treated with imatinib. Bone density tended to be higher than age and gender-matched normal values. These data suggest that nilotinib may have important effects on bone metabolism. Prospective studies should be conducted to determine the long-term effects of nilotinib on bone density and calcium metabolism.

    View record details
  • The skeletal effects of the tyrosine kinase inhibitor nilotinib

    O'Sullivan, Susannah; Lin, JM; Watson, Maureen; Callon, Karen; Tong, PC; Naot, Dorit; Horne, Anne; Aati, O; Porteous, F; Gamble, Gregory; Cornish, Jillian; Browett, Peter; Grey, Andrew (2011)

    Journal article
    The University of Auckland Library

    Nilotinib is a tyrosine kinase inhibitor (TKI) developed to manage imatinib-resistance in patients with chronic myeloid leukemia (CML). It inhibits similar molecular targets to imatinib, but is a significantly more potent inhibitor of Bcr-Abl. Nilotinib exhibits off-target effects in other tissues, and of relevance to bone metabolism, hypophosphataemia has been reported in up to 30% of patients receiving nilotinib. We have assessed the effects of nilotinib on bone cells in vitro and on bone metabolism in patients receiving nilotinib for treatment of CML. We firstly investigated the effects of nilotinib on proliferating and differentiating osteoblastic cells, and on osteoclastogenesis in murine bone marrow cultures and RAW264.7 cells. Nilotinib potently inhibited osteoblast proliferation (0.01???1 uM), through inhibition of the platelet-derived growth factor (PDGFR). There was a biphasic effect on osteoblast differentiation such that it was reduced by lower concentrations of nilotinib (0.1???0.5 uM), with no effect at higher concentrations (1 uM). Nilotinib also potently inhibited osteoclastogenesis, predominantly by stromal-cell dependent mechanisms. Thus, nilotinib decreased osteoclast development in murine bone marrow cultures, but did not affect osteoclastogenesis in RAW264.7 cells. Nilotinib treatment of osteoblastic cells increased expression and secretion of OPG and decreased expression of RANKL. In 10 patients receiving nilotinib, levels of bone turnover markers were in the low-normal range, despite secondary hyperparathyroidism, findings that are similar to those in patients treated with imatinib. Bone density tended to be higher than age and gender-matched normal values. These data suggest that nilotinib may have important effects on bone metabolism. Prospective studies should be conducted to determine the long-term effects of nilotinib on bone density and calcium metabolism.

    View record details
  • Urate crystal deposition in asymptomatic hyperuricaemia and symptomatic gout: a dual energy CT study

    Dalbeth, Nicola; House, ME; Aati, O; Tan, P; Franklin, C; Horne, Anne; Gamble, Gregory; Stamp, LK; Doyle, Anthony; McQueen, Fiona (2015-05)

    Journal article
    The University of Auckland Library

    BACKGROUND: The aim of this study was to compare the frequency and volume of dual energy CT (DECT) urate deposits in people with asymptomatic hyperuricaemia and symptomatic gout. METHODS: We analysed DECT scans of the feet from asymptomatic individuals with serum urate ???540?????mol/L (n=25) and those with crystal proven gout without clinically apparent tophi (n=33). RESULTS: DECT urate deposits were observed in 6/25 (24%) participants with asymptomatic hyperuricaemia, 11/14 (79%) with early gout (predefined as disease duration ???3???years) and 16/19 (84%) with late gout (p<0.01 for both comparisons). Similar urate volumes were observed in the early and late gout groups. CONCLUSIONS: Although subclinical urate deposition can occur in people with asymptomatic hyperuricaemia, these deposits occur more frequently and at higher volumes in those with symptomatic gout. These data suggest that a threshold of urate crystal volume may be required before symptomatic disease occurs.

    View record details
  • Relationship of bone erosion with the urate and soft tissue components of the tophus in gout: a dual energy computed tomography study

    Sapsford, M; Gamble, Gregory; Aati, O; Knight, J; Horne, Anne; Doyle, Anthony; Dalbeth, Nicola (2017-01)

    Journal article
    The University of Auckland Library

    OBJECTIVES: Imaging and pathology studies have established a close relationship between tophus and bone erosion in gout. The tophus is an organized structure consisting of urate crystals and chronic inflammatory tissue. The aim of this work was to examine the relationship between bone erosion and each component of the tophus. METHODS: Plain radiographs and dual energy CT scans of the feet were prospectively obtained from 92 people with tophaceous gout. The 10 MTP joints were scored for erosion score, tophus urate and soft tissue volume. Data were analysed using generalized estimating equations and mediation analysis. RESULTS: Tophus was visualized in 80.2% of all joints with radiographic (XR) erosion [odds ratio (OR) = 7.1 (95% CI: 4.8, 10.6)] and urate was visualized in 78.6% of all joints with XR erosion [OR = 6.6 (95% CI: 4.7, 9.3)]. In mediation analysis, tophus urate volume and soft tissue volume were directly associated with XR erosion score. About a third of the association of the tophus urate volume with XR erosion score was indirectly mediated through the strong association between tophus urate volume and tophus soft tissue volume. CONCLUSION: Urate and soft tissue components of the tophus are strongly and independently associated with bone erosion in gout.

    View record details
  • Path Analysis Identifies Receptor Activator of Nuclear Factor-??B Ligand, Osteoprotegerin, and Sclerostin as Potential Mediators of the Tophus-bone Erosion Relationship in Gout

    Chhana, Ashika; Aati, O; Gamble, Gregory; Callon, Karen; Doyle, Anthony; Roger, M; McQueen, Fiona; Horne, Anne; Reid, Ian; Cornish, Jillian; Dalbeth, Nicola (2016-02)

    Journal article
    The University of Auckland Library

    Objective. To determine the relationship between tophus, erosion and bone remodeling factors in gout. Methods. Computed tomography bone erosion and circulating bone factors were measured in adults with tophaceous gout. Multiple regression modeling and path analysis were used to determine predictors of erosion. Results. Tophus number, M??ori or Pacific ethnicity, creatinine, receptor activator of nuclear factor-??B ligand (RANKL), osteoprotegerin (OPG), and sclerostin were independently associated with erosion. Path analysis showed a direct effect of tophus number on erosion, partially mediated through OPG, RANKL, and sclerostin. Conclusion. Tophus number is strongly associated with bone erosion in gout. Circulating RANKL, OPG, and sclerostin are potential mediators of tophus-related erosion.

    View record details