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RNA-Seq analysis unveils differential gene expression patterns following intermittent hypoxia in the mandibular condyles of growing male rats

ABSTRACT: Intermittent hypoxia, which is a characteristic of obstructive sleep apnea can impair mandibular growth during early development, particularly in infants. This study aimed to investigate gene expression profiles associated with mandibular cartilage growth in infant male rats exposed to IH modeling pediatric OSA. We used eight-day-old male Sprague-Dawley rats were subjected to either normoxic air or IH and sacrificed after 1 week. Mandibular growth was evaluated using micro-computed tomography and histomorphometry. RNA sequencing examined differential gene expression in bone and cartilage. IH caused mandibular growth deficits, including reduced total cartilage thickness in the mid- and posterior mandibular condylar regions. Comparative measurements between IH and normoxia showed thinning of all cartilage layers in these regions under IH. In contrast, the anterior region exhibited thicker proliferative and maturative layers but a thinner hypertrophic layer under IH. RNA sequencing identified 342 upregulated and 45 downregulated genes in the IH group, including key regulators of bone and cartilage metabolism, such as gremlin-2, fibroblast growth factor 2, insulin-like growth factor binding protein 2, interleukin-1B, bone gamma-carboxyglutamate protein, wingless-related integration site 2, and SRY-box transcription factor 11. These findings suggest that IH alters expression of critical genes in mandibular cartilage development, potentially contributing to growth deficits.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE333533 | GEO | 2026/05/28

REPOSITORIES: GEO

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Project description:Background Extracellular matrix (ECM) protein malfunction or defect may lead to temporomandibular joint osteoarthritis (TMJ OA). Dentin sialophophoprotein (DSPP) is a mandibular condylar cartilage ECM protein, and its deletion impacted cell proliferation and other extracellular matrix alterations of postnatal condylar cartilage. However, it remains unclear if long-term loss of function of DSPP leads to TMJ OA. The study aimed to test the hypothesis that long-term haploinsufficiency of DSPP causes TMJ OA. Materials and Methods To determine whether Dspp+/- mice exhibit TMJ OA but no severe tooth defects, mandibles of wild-type (WT), Dspp+/-, and Dspp homozygous (Dspp-/-) mice were analyzed by Micro-computed tomography (micro-CT). To characterize the progression and possible mechanisms of osteoarthritic degeneration over time in Dspp+/- mice over time, condyles of Dspp+/- and WT mice were analyzed radiologically, histologically, and immunohistochemically. Results Micro-CT and histomorphometric analyses revealed that Dspp+/- and Dspp-/- mice had significantly lower subchondral bone mass, bone volume fraction, bone mineral density, and trabecular thickness compared to WT mice at 12 months. Interestingly, in contrast to Dspp-/- mice which exhibited tooth loss, Dspp+/- mice had minor tooth defects. RNA sequencing data showed that haplodeficency of DSPP affects the biological process of ossification and osteoclast differentiation. Additionally, histological analysis showed that Dspp+/- mice had condylar cartilage fissures, reduced cartilage thickness, decreased articular cell numbers and severe subchondral bone cavities, and with signs that were exaggerated with age. Radiographic data showed an increase in subchondral osteoporosis up to 18 months and osteophyte formation at 21 months. Moreover, Dspp+/- mice showed increased distribution of osteoclast in the subchondal bone and increased expression of MMP2, IL-6, FN-1, and TLR4 in the mandibular condylar cartilage. Conclusions Dspp+/- mice exhibit TMJ OA in a time-dependent manner, with lesions in the mandibular condyle attributed to hypomineralization of subchondral bone and breakdown of the mandibular condylar cartilage, accompanied by upregulation of inflammatory markers.

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RNA-Seq analysis unveils differential gene expression patterns following intermittent hypoxia in the mandibular condyles of growing male rats

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