TIMP3 Modulates GHR Abundance and GH Sensitivity.

GH receptor (GHR) binds GH at the cell surface via its extracellular domain and initiates intracellular signal transduction, resulting in important anabolic and metabolic actions. GH signaling is subject to dynamic regulation, which in part is exerted by modulation of cell surface GHR levels. Constitutive and inducible metalloprotease-mediated cleavage of GHR regulate GHR abundance and thereby modulate GH action. We previously demonstrated that GHR proteolysis is catalyzed by the TNF-α converting enzyme (TACE; ADAM17). Tissue inhibitors of metalloproteases-3 (TIMP3) is a natural specific inhibitor of TACE, although mechanisms underlying this inhibition are not yet fully understood. In the current study, we use two model cell lines to examine the relationships between cellular TACE, TIMP3 expression, GHR metalloproteolysis, and GH sensitivity. These two cell lines exhibited markedly different sensitivity to inducible GHR proteolysis, which correlated directly to their relative levels of mature TACE vs unprocessed TACE precursor and indirectly to their levels of cellular TIMP3. Our results implicate TIMP3 as a modulator of cell surface GHR abundance and the ability of GH to promote cellular signaling; these modulatory effects may be conferred by endogenous TIMP3 expression as well as exogenous TIMP3 exposure. Furthermore, our analysis suggests that TIMP3, in addition to regulating the activity of TACE, may also modulate the maturation of TACE, thereby affecting the abundance of the active form of the enzyme.

Use of permanently placed metal expandable cages for vertebral body reconstruction in the surgical treatment of spondylodiscitis.

This is a retrospective study of 15 patients treated for spondylodiscitis with implanted metal cages. The purpose of this study is to investigate the outcomes of patients treated with permanently placed metal hardware in vertebral body reconstruction for spondylodiscitis. The use of metal implants in the face of infection has classically been discouraged in orthopedic literature because of the ability of bacteria to form biofilms on metal surfaces. Traditional treatment of spondylodiscitis has been aggressive debridement followed by reconstruction with bone grafts. Expandable metallic cages made reconstruction of these defects significantly easier. However, concern exists that metallic implants affect the resolution of infection. A search of the authors' patient database from 2005 to 2009 revealed 21 patients with spondylodiscitis treated with anterior debridement and reconstruction with an expandable metallic cage. Fourteen patients (15 cases) had sufficient documented clinical follow-up and were available for review. Resolution of infection was determined by evaluating symptoms, laboratory data, and final radiographic result. Of the 15 cases, all had clinical resolution of infection with an average follow-up time of 25 months. An average loss of 1.9° of correction was observed when comparing final follow-up radiographs with initial postoperative radiographs. Radiograph review revealed no extensive osteolysis around the hardware or progressive collapse. These results suggest that the use of expandable metal cages maintains alignment while not perpetuating infection. The spine appears to provide a unique environment that permits the use of metal implants in the setting of infection.