Osteoarthritis (OA) is the most common chronic joint disease and leads to the degradation of the extracellular matrix by an imbalance between anabolic and catabolic processes. TGF-β3 (transforming growth factor beta-3) and epidermal growth factor (EGF) influence the osteochondrogenic potential of chondrocytes. In this study, we compared the expression of mediators and receptors in the TGF-β3 and EGF pathways, as well as biglycan (BGN), in healthy and diseased chondrocytes. Furthermore, we used chondrogenic progenitor cells (CPCs) for in vitro stimulation and knockdown experiments to elucidate the effects of TGF-β3 and EGF on the chondrogenic potential. Our results demonstrate that the expression of TGF-beta receptor type-1 (TGFBRI) and epidermal growth factor receptor (EGFR) is altered in diseased chondrocytes as well as in CPCs. Moreover, TGF-β3 and EGF stimulation influenced the expression levels of BGN, SRY (sex determining region Y)-box 9 (SOX9), and Runt-related transcription factor 2 (RUNX2) in CPCs. Therefore, changes in TGFBRI and EGFR expression likely contribute to the degenerative and regenerative effects seen in late stages of OA. (J Histochem Cytochem 67:117-127, 2019)

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IntroductionBoth the calvarial and the cortical bones develop through intramembranous ossification, yet they have very different structures and functions. The calvaria enables the rapid while protected growth of the brain, whereas the cortical bone takes part in locomotion. Both types of bones undergo extensive modeling during embryonic and post-natal growth, while bone remodeling is the most dominant process in adults. Their shared formation mechanism and their highly distinct functions raise the fundamental question of how similar or diverse the molecular pathways that act in each bone type are.MethodsTo answer this question, we aimed to compare the transcriptomes of calvaria and cortices from 21-day old mice by bulk RNA-Seq analysis.ResultsThe results revealed clear differences in expression levels of genes related to bone pathologies, craniosynostosis, mechanical loading and bone-relevant signaling pathways like WNT and IHH, emphasizing the functional differences between these bones. We further discussed the less expected candidate genes and gene sets in the context of bone. Finally, we compared differences between juvenile and mature bone, highlighting commonalities and dissimilarities of gene expression between calvaria and cortices during post-natal bone growth and adult bone remodeling.DiscussionAltogether, this study revealed significant differences between the transcriptome of calvaria and cortical bones in juvenile female mice, highlighting the most important pathway mediators for the development and function of two different bone types that originate both through intramembranous ossification.

Summary Osteoarthritis (OA) is the most prevalent chronic joint disease that affects a large proportion of the elderly population. Chondrogenic progenitor cells (CPCs) reside in late-stage OA cartilage tissue, producing a fibrocartilaginous extracellular matrix; these cells can be manipulated in vitro to deposit proteins of healthy articular cartilage. CPCs are under the control of SOX9 and RUNX2. In our earlier studies, we showed that a knockdown of RUNX2 enhanced the chondrogenic potential of CPCs. Here we demonstrate that CPCs carrying a knockout of RAB5C, a protein involved in endosomal trafficking, exhibited elevated expression of multiple chondrogenic markers, including the SOX trio, and increased COL2 deposition, whereas no changes in COL1 deposition were observed. We report RAB5C as an attractive target for future therapeutic approaches designed to increase the COL2 content in the diseased joint.