Overexpression of Smurf2 Stimulates Endochondral Ossification Through Upregulation of β-Catenin

Abstract

Ectopic expression of Smurf2 in chondrocytes and perichondrial cells accelerated endochondral ossification by stimulating chondrocyte maturation and osteoblast development through upregulation of ␤-catenin in Col2a1-Smurf2 embryos. The mechanism underlying Smurf2-mediated morphological changes during embryonic development may provide new mechanistic insights and potential targets for prevention and treatment of human osteoarthritis. Introduction: Our recent finding that adult Col2a1-Smurf2 mice have an osteoarthritis-like phenotype in knee joints prompted us to examine the role of Smurf2 in the regulation of chondrocyte maturation and osteoblast differentiation during embryonic endochondral ossification. Materials and Methods: We analyzed gene expression and morphological changes in developing limbs by immunofluorescence, immunohistochemistry, Western blot, skeletal preparation, and histology. A series of markers for chondrocyte maturation and osteoblast differentiation in developing limbs were examined by in situ hybridization. Results: Ectopic overexpression of Smurf2 driven by the Col2a1 promoter was detected in chondrocytes and in the perichondrium/periosteum of 16.5 dpc transgenic limbs. Ectopic Smurf2 expression in cells of the chondrogenic lineage inhibited chondrocyte differentiation and stimulated maturation; ectopic Smurf2 in cells of the osteoblastic lineage stimulated osteoblast differentiation. Mechanistically, this could be caused by a dramatic increase in the expression of ␤-catenin protein levels in the chondrocytes and perichondrial/ periosteal cells of the Col2a1-Smurf2 limbs. Conclusions: Ectopic expression of Smurf2 driven by the Col2a1 promoter accelerated the process of endochondral ossification including chondrocyte maturation and osteoblast differentiation through upregulation of ␤-catenin, suggesting a possible mechanism for development of osteoarthritis seen in these mice.

Ectopic expression of Smurf2 and acceleration of age-related intervertebral disc degeneration in a mouse model

“…43,45 Meanwhile, we also found that meniscus degeneration progresses at a pace similar to that of articular cartilage degeneration in these mice (Fig. 1).…”

“…Adult mouse knee joints and lumbar spine tissues were prepared for histology as described previously. 43,45 Briefly, adult mouse knee joints and lumbar spine tissues were fixed, decalcified, and embedded in either paraffin or optimal cutting temperature compound (OCT). Five-and 10-mm-thick sections were cut for paraffin and OCT blocks, respectively, and 4-6 serial sagittal paraffin sections were harvested every 30 mm apart within the midsagittal region of knee joints and intervertebral bodies.…”

Early Cartilage Degeneration in a Rat Experimental Model of Developmental Dysplasia of the Hip

“…The articular cartilage is a permanent tissue, with minimal turnover of its cells and matrix. In normal articular cartilage, the matrix is a highly hydrated network of collagen fibrils embedded in a gel of negatively charged proteoglycan molecules [14,15]. During infancy and early childhood there is increased turnover of type II collagen in the articular cartilage.…”

Scaffold‐Based microRNA Therapies in Regenerative Medicine and Cancer

“…[96] Although little is known regarding the uptake mechanisms of CaP-nucleic acid complexes, their ability to form precipitates on the cell surface and undergo clathrin and dynamin-dependent endocytosis has been documented, [37] and their pH-dependent solubility allows complex dissociation to commence within intracellular compartments. [97] Considering the ease of production, cost effectiveness and high biocompatibility of CaPs, [98] together with the newly improved efficiency of these nHA particles to deliver miRNA therapeutics, the proposed system has demonstrated a substantial potential for the derivation of new therapeutics in this field.…”