Peri-cellular remodeling of mesenchymal extracellular matrices is considered a prerequisite for cell proliferation, motility and development. Here we demonstrate that membrane-type 3 MMP, MT3-MMP, is expressed in mesenchymal tissues of the skeleton and in peri-skeletal soft connective tissue. Consistent with this localization, MT3-MMP-deficient mice display growth inhibition tied to a decreased viability of mesenchymal cells in skeletal tissues. We document that MT3-MMP works as a major collagenolytic enzyme, enabling cartilage and bone cells to cleave high-density fibrillar collagen and modulate their resident matrix to make it permissive for proliferation and migration. Collectively, these data uncover a novel extracellular matrix remodeling mechanism required for proper function of mesenchymal cells. The physiological significance of MT3-MMP is highlighted in mice double deficient for MT1-MMP and MT3-MMP. Double deficiency transcends the combined effects of the individual single deficiencies and leads to severe embryonic defects in palatogenesis and bone formation incompatible with life. These defects are directly tied to loss of indispensable collagenolytic activities required in collagen-rich mesenchymal tissues for extracellular matrix remodeling and cell proliferation during embryogenesis.

The existing literature regarding PTH levels to predict postthyroidectomy hypocalcemia is extremely heterogeneous. A single PTH threshold is not a reliable measure of hypocalcemia. Additional prospective studies controlled for timing of laboratory draws and a priori defined PTH thresholds need to be performed to ascertain the true prognostic significance of PTH in predicting postthyroidectomy hypocalcaemia.

IntroductionAfter embryo implantation and decidualization, a critical step in placental development is the formation of the placental labyrinth (LA), which enables nutrient and gas exchange between the embryonic vasculature and the maternal blood supply. 1-5 LA formation is associated with substantial tissue remodeling and cell differentiation, as well as ingrowth of the embryonic vasculature through the chorion to a point of immediate proximity with the maternal blood supply. During this process, chorionic trophoblasts (CHs) differentiate into 2 perivascular cell populations that form distinct bilaminar envelopes of syncytiotrophoblasts in immediate contact with the fetal vascular endothelium. 6 Multiple transcription factors, growth factors, adhesion molecules, and gap junction molecules are known to influence the formation of the LA. 7 Interestingly, few if any proteolytic enzymes have so far been proven essential for LA formation although tissue remodeling is considered an integral part of this morphogenetic process. Several of the matrix metalloproteinases (MMPs), cathepsins, and serine proteinases are expressed in the placenta during development, however to date none have proven indispensable for development of the LA and in turn development of the embryo to term. [8][9][10][11][12] Among the 6 known membrane-type MMP (MT-MMP) molecules in the mouse, MT1-MMP and MT3-MMP possess pericellular collagenase activity and are required for both prenatal and postnatal remodeling of the major fibrillar collagen types, cell surface receptors, and signaling molecules. [13][14][15] Ablation of MT1-MMP deprives cells of the ability to migrate through and process several both permanent and provisional extracellular matrices, and in vivo leads to severe defects in postnatal remodeling of connective tissues. [16][17][18][19] Moreover, MT1-MMP is required in the stromal compartment for efficient dissemination of malignant epithelial cells in mouse mammary carcinoma. 20 MT1-MMP deficiency is partially mitigated by the activity of the molecular relative, MT3-MMP, which shares at least some overlapping substrate specificity with MT1-MMP. Accordingly, incremental loss of alleles encoding each molecule markedly exacerbates the cellular matrix remodeling deficit in a gene dosage dependent manner, and double deficiency results in severe developmental deficits and perinatal death, but importantly, not preterm loss of embryos. 15 As expected from these observations, MT1-MMP and MT3-MMP are frequently coexpressed in the same tissue compartments. The placental LA however is devoid of MT3-MMP expression but displays conspicuous expression of another MT-MMP family member, MT2-MMP. 11,21 So far, the function of MT2-MMP has been determined biochemically and in cell-based assays. Under these conditions, MT2-MMP displays the ability to process basement membrane components and fibrillar collagen matrices whereas its role in vivo has remained unexplored. 22,23 Here we demonstrate that MT2-MMP deficiency in the mouse is compatible with develop...

Following total thyroidectomy, PTH levels are unreliable in predicting hypocalcemia. Additional prospective studies are needed to understand the true utility of PTH levels post-thyroidectomy.