Retention of the Matricellular Protein SPARC in the Endoplasmic Reticulum of Chondrocytes from Patients with Pseudoachondroplasia

Abstract

S U M M A R Y Pseudoachondroplasia (PSACH) is an autosomal dominant disease characterized by dwarfism, morphological irregularities of long bones and hips, and early-onset osteoarthritis. This disease has been attributed to mutations in a structural protein of the cartilage extracellular matrix (ECM), cartilage oligomeric matrix protein (COMP), which result in its selective retention in the chondrocyte rough endoplasmic reticulum (ER). Accumulation of excessive amounts of mutated COMP might reflect a defect in protein trafficking by PSACH chondrocytes. Here we identify the matricellular protein SPARC as a component of this trafficking deficit. SPARC was localized to the hypertrophic chondrocytes in the normal human tibial growth plate and in cultured control cartilage nodules. In contrast, concentrated intracellular depots of SPARC were identified in nodules cultured from three PSACH patients with mutations in COMP. The accumulated SPARC was coincident with COMP and with protein disulfide isomerase, a resident chaperone of the rough ER, whereas SPARC and COMP were not coincident in the ECM of control or PSACH nodules. SPARC-null mice develop severe osteopenia and degenerative intervertebral disc disease, and exhibit attenuation of collagenous ECM. The retention of SPARC in the ER of chondrocytes producing mutant COMP indicates a new intracellular function for SPARC in the trafficking/secretion of cartilage ECM. (J Histochem Cytochem 54:269-274, 2006)

Periostin Associates with Notch1 Precursor to Maintain Notch1 Expression under a Stress Condition in Mouse Cells

“…Recently, the possibility of an intracellular function of matricellular proteins was proposed, since (1) SPARC is located primarily intracellularly in non-pathological tissues, and is coincidently located with protein disulfide isomerase (PDI), a ER-resident protein, in pseudoachondroplasia chondrocytes [20], and (2) periostin appeared to be anchored in the Golgi [21]. In light of these previous studies, we can hypothesize an intracellular function of matricellular proteins active in the membrane trafficking pathway.…”

Invoking the power of thrombospondins: Regulation of thrombospondins expression

“…Although some of them, e.g., TSP-1, TSP-4 and TSP-5, perform important functions inside the secretory pathways (25, 122-124), most of the widely known functions rely on the presence of TSPs outside the cell.…”

“…Both TSP-4 and TSP-5 appear to have additional intracellular functions in the secretory pathways: TSP-5 can associate with its co-secreted extracellular ligands and ER chaperones (122-124), and TSP-4 bind a transcriptional factor Aft6α promoting its translocation to the nucleus (25). The latter function is shared with TSP-1 and is thought to be a common feature of TSPs in protecting and augmenting ER function (25).…”

Transgenic mice expressing D469Δ mutated cartilage oligomeric matrix protein (COMP) show growth plate abnormalities and sternal malformations

“…The accumulation of COMP leads to a selective co-retention of other matrix components like aggrecan, decorin, fibromodulin, SPARC, matrilin-3, collagen IX, XI and XII, while collagen II and VI are still secreted (Hecht et al, 2005;Hecht and Sage, 2006;Maddox et al, 1997;Vranka et al, 2001). Experiments with isolated PSACH chondrocytes suggest that the inclusions in the rough endoplasmic reticulum develop slowly over time (Delot et al, 1998).…”