The Natural History of Asymptomatic Deep Pars Tensa Retraction.

OBJECTIVES: The aim of this study was to quantify the natural behavior of asymptomatic deep pars tensa retraction in both adults and children. MATERIALS AND METHODS: Asymptomatic pars tensa retraction pockets that contacted the promontory were included. Persistently symptomatic pars tensa retraction, pars tensa retraction that did not contact the promontory, patients with attic retraction pockets and patients with cholesteatoma were excluded. Patients were followed up annually and were eliminated from the study if they required active intervention or recovered so that their ears were persistently ventilated with no contact of the tympanic membrane to the promontory. Outcome variables included surgical intervention, surgical intervention for cholesteatoma, and spontaneous improvement and were studied using the life table method. RESULTS: In total, 64 children and 25 adults were enrolled, of whom 19 children and five adults required intervention and five children and two adults developed pars tensa cholesteatomas. No significant difference was observed between children and adults. In total, three children, but no adults, developed attic cholesteatomas without progression of the pars tensa disease. Furthermore, the ears of 20 children, but not even one adult ear, returned to normal over the 10-year study period. DISCUSSION: Most retracted adult ears did not change. Over 10 years, the most common finding in children was the return of their ears to normal. Ear of all children recovered during the second decade. Deterioration to form cholesteatoma was not influenced by age. Attic cholesteatoma without the progression of pars tensa disease was observed in children, but not in adults.

The synergistic effects of lysophosphatidic acid receptor agonists and calcitriol on MG63 osteoblast maturation at titanium and hydroxyapatite surfaces.

Successful osseointegration stems from the provision of a mechanically competent mineralised matrix at the implant site. Mature osteoblasts are the cells responsible for achieving this and a key factor for ensuring healthy bone tissue is associated with prosthetic materials will be 1 alpha,25 dihydroxy vitamin D3 (calcitriol). However it is known that calcitriol per se does not promote osteoblast maturation, rather the osteoblasts need to be in receipt of calcitriol in combination with selected growth factors in order to undergo a robust maturation response. Herein we report how agonists of the lysophosphatidic acid (LPA) receptor, LPA and (2S)-OMPT, synergistically co-operate with calcitriol to secure osteoblast maturation for cells grown upon two widely used bone biomaterials, titanium and hydroxyapatite. Efforts could now be focussed on functionalizing these materials with LPA receptor agonists to support in vivo calcitriol-induced osseointegration via heightened osteoblast maturation responses.

Lithocholate--a promising non-calcaemic calcitriol surrogate for promoting human osteoblast maturation upon biomaterials.

BACKGROUND AND AIMS: Calcitriol, an active vitamin D metabolite, has a limited application in bone repair because of its undesirable hypercalcaemic action. However it has emerged that lithocholic acid (LCA) is a non-calcaemic vitamin D receptor ligand but whether this steroid can support osteoblast maturation has not been reported. Using the human osteoblast cell line, MG63, we explored the potential of LCA and LCA derivatives to secure osteoblast maturation. RESULTS: The co-stimulation of cells with LCA, LCA acetate or LCA acetate methyl ester (0.5-5 microM) and lysophosphatidic acid (LPA, 20 microM) resulted in clear, synergistic increases in MG63 maturation that was both time and dose dependent. Cells grown upon both titanium and hydroxyapatite, two widely used implant materials, responded well to co-treatment with LCA acetate (5 microM) and LPA (20 microM) as demonstrated by stark, synergistic increases in ALP activity. Evidence of activator protein-1 (AP-1) stimulation by LCA acetate (30 microM) was demonstrated using an AP-1 luciferase reporter assay. Synergistic increases in ALP activity, and therefore osteoblast maturation, were observed for MG63 cells co-stimulated with LCA acetate (5 microM) and either epidermal growth factor (10 ng/ml) or transforming growth factor-beta (10 ng/ml). Ligands acting on either the farnesoid X receptor or pregnane X receptor could not substitute for the action of LCA acetate on MG63 maturation. CONCLUSIONS: Lithocholate is able to act as a calcitriol surrogate in generating mature osteoblasts. Given that LCA is non-calcaemic it is likely to find an application in bone repair/regeneration by aiding matrix calcification at implant sites.

Cytoskeletal reorganisation, 1alpha,25-dihydroxy vitamin D3 and human MG63 osteoblast maturation.

Bone tissue is especially receptive to physical stimulation and agents with the capacity to mimic the signalling incurred via mechanical loading on osteoblasts may find an application in a bone regenerative setting. Recently this laboratory revealed that the major serum lipid, lysophosphatidic acid (LPA), co-operated with 1alpha,25-dihydroxy vitamin D3 (D3) in stimulating human osteoblast maturation. Actin stress fiber accrual in LPA treated osteoblasts would have generated peripheral tension which in turn may have heightened the maturation response of these cells to D3. To test this hypothesis we examined if other agents known to trigger stress fiber accumulation co-operated with D3 in stimulating human osteoblast maturation. Colchicine, nocodazole and LPA all co-operated with D3 to promote MG63 maturation in a MEK dependent manner. In contrast, calpeptin, a direct activator of Rho kinase and stress fiber accumulation did not act with D3 to secure MG63 differentiation. Herein we describe how the signalling elicited via microtubule disruption cooperates with D3 in the development of mature osteoblasts.