Friday, October 21, 2011


Site-1 Protease Is Essential to Growth Plate Maintenance and Is a Critical Regulator of Chondrocyte Hypertrophic Differentiation in Postnatal Mice

"Site-1 protease (S1P) is a proprotein convertase with essential functions in lipid homeostasis and unfolded protein response pathways. We previously studied a mouse model of cartilage-specific knock-out of S1P in chondroprogenitor cells. These mice exhibited a defective cartilage matrix devoid of type II collagen protein (Col II) and displayed chondrodysplasia with no endochondral bone formation even though the molecular program for endochondral bone development appeared intact. To gain insights into S1P function, we generated and studied a mouse model in which S1P is ablated in postnatal chondrocytes. Postnatal ablation of S1P results in chondrodysplasia. However, unlike early embryonic ablations, the growth plates of these mice exhibit a lack of Ihh, PTHrP-R, and Col10 expression indicating a loss of chondrocyte hypertrophic differentiation and thus disruption of the molecular program required for endochondral bone development. S1P ablation results in rapid growth plate disruption due to intracellular Col II entrapment concomitant with loss of chondrocyte hypertrophy suggesting that these two processes are related. Entrapment of Col II in the chondrocytes of the prospective secondary ossification center precludes its development. Trabecular bone formation is dramatically diminished in the primary spongiosa and is eventually lost. The primary growth plate is eradicated by apoptosis but is gradually replaced by a fully functional new growth plate from progenitor stem cells capable of supporting new bone growth. S1P has fundamental roles in the preservation of postnatal growth plate through chondrocyte differentiation and Col II deposition and functions to couple growth plate maturation to trabecular bone development in growing mice. "

"During unfolded protein response, S1P is involved in the maturation of the endoplasmic reticulum membrane-bound transcription factors ATF6, old astrocyte specifically induced substance, and cAMP-responsive element-binding protein H"

"Arrows in H and K point to the SOC (also see P) that is pushed aside to accommodate the additional growth plate shown in P7–P28 mutants (P) with normal hypertrophic (h) cells (R). The arrow in R points to the dead, inactive primary growth plate. In the older P7–P42 mutant mice, this new growth plate allows for development of new trabecular bone (arrowheads in I, L, and T), which is now aligned with the cortical bone (arrow in I and T) due to bending of the distal femur."

Although the fact that this took place in embryos could mean that the mechanisms of this neo growth plate formation are not the same as those present in an adult.

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