Discovery of molecular mechanisms underlying chondrogenesis is necessary to develop
therapies for skeletal disorders and articular cartilage defects or disorders like
osteoarthritis (OA). Specific properties of each tissue are derived from tissue-specific
gene expression. Therefore, it is likely that genes with tissue-specific expression have an
important role in development of structural and functional properties of tissue.
Remarkable number of genes associated with OA and genetic skeletal disorders have a
cartilage-selective expression pattern. Some of these are proteoglycans (PG), which are
important structural components of cartilage extracellular matrix (ECM) and modulators
of activity of extracellular signal molecules.
The aim of the study was to discover novel genes essential in chondrogenesis and
cartilage homeostasis by transcriptional profiling. Of the large-scale analysis, a promising
transcript named Snorc (small novel rich in cartilage), was selected for more specific
analysis. The aim of the analysis was to define expression and structure of Snorc gene
and protein, to define interaction partners of Snorc protein and to analyze the role of the
Snorc gene in mouse skeletal tissue development.
Snorc is a type I single-pass transmembrane chondroitin or dermatan sulfate PG, highly
conserved in vertebrates. Expression of Snorc was observed throughout life span in mouse
epiphysis especially during development. Expression is most intense in proliferative and
prehypertrophic cartilage of growth plate (GP) during embryonic development, and in
prehypertrophic chondrocytes surrounding secondary ossification center (SOC) during
postnatal development. Messenger RNA is cartilage-specific, but immunoreactivity was
detected also in ECM of trabecular bone. Size of mineralized SOC is decreased and structure
of GP disturbed in Snorc-deficient mice knee epiphysis, compared to wild type (WT).
Proliferative and hypertrophic zones were enlarged, especially in medial part, and
chondrocyte morphology was changed in Snorc-deficient mice GP at postnatal day (P) 10
and 22. Indian hedgehog (Ihh) and collagen type X alpha 1 chain (Col10a1) expression were
increased and matrix metalloproteinase 13 (Mmp13) decreased in P10 Snorc-deficient mouse
epiphysis. Peripheral quantitative tomography revealed increase in endosteal and in periosteal
perimeter, and in the area of trabecular bone in the cross-section of distal femoral metaphysis
in adult Snorc-deficient mice compared to WT. However, alterations in long bone length were
not observed. Bone morphogenetic protein 2 induced expression of Snorc in chondrocytes.
Snorc extracellular domain (ECD) binds fibroblastic growth factor 2 (Fgf2) independently of
glycosaminoglycan chain of Snorc.
Snorc is a novel cartilage-specific transmembrane PG with a role in maturation of
postnatal GP chondrocytes, epiphyseal ossification and metaphyseal bone formation in
mouse. Snorc-deficiency caused alterations in expression of Ihh and Mmp13 genes in
postnatal epiphysis. Ihh is important regulator of proliferative zone and Mmp13 necessary
for vascularization and ossification of cartilage. Binding of Fgf2 to Snorc ECD clues that
Snorc may have a role in Fgf signaling potentially as a coreceptor.