Shammas, H. | Search bioRxiv

bioRxiv2026

PRDM16 Coordinates Genetic and Epigenetic Programs Governing Chondrogenesis and Chondrocyte Phenotype Specification in the Knee Joint

Cartilage development and homeostasis require precise regulation by transcriptional and epigenetic networks. PRDM16 is a transcription factor containing zinc finger domains that enable protein-DNA and protein-protein interactions, as well as domains with the capacity for histone methyltransferase activity. However, the detailed molecular mechanisms by which PRDM16 regulates chondrogenesis and chondrocyte identities remain largely unknown. Using our osteochondral lineage-specific, conditional knockout mouse model (Col2a1Cre;Prdm16flox/flox, Prdm16 cKO), we found that loss of Prdm16 in osteochondral lineage cells delays, but does not fully inhibit, endochondral ossification and bone formation in the knee joint. Furthermore, Prdm16 cKO male mice exhibit comparable OA severity between injured and non-injured joints, suggesting that PRDM16 may exert a chondroprotective function. In our hiPSC-derived chondrocyte model, we observed significantly reduced pellet size and DNA content in cells with modulated PRDM16 expression compared to Control, implying a link between PRDM16 and chondrocyte viability. Integrated analysis of single cell RNA-sequencing and CUT&RUN-sequencing revealed that PRDM16 regulates chondrocyte cell fate decisions by altering chromatin accessibility and DNA binding at promoter/enhancer regions of genes essential for chondrogenesis and chondrocyte hypertrophy. Indeed, PRDM16 governs the expression of key chondrogenic regulators including SOX9, ARID5A, SMOC2, HAND2, and hypertrophic driver MEF2C. Overall, our results provide evidence that PRDM16 serves as an essential genetic and epigenetic regulator of chondrogenesis and chondrocyte phenotype specification in the knee joint through DNA binding and by modulating H3K4me3 histone mark deposition.

pathology↗

bioRxiv2022

A Murine Model of Abductor Insufficiency Accelerates the Development of Hip Osteoarthritis

Osteoarthritis (OA) of the hip is a common and debilitating painful joint disease. A growing body of evidence suggests that there may be an association between periarticular myotendinous pathology and the development of hip OA. Thus, we hypothesized that a murine model of hip OA could be achieved through selective injury of the abductor complex around the hip. C57BL6/J mice were randomized to sham surgery or abductor injury, in which the myotendinous insertion at the third trochanter and greater trochanter were surgically detached. Mice were allowed free, active movement until sacrifice at either 3 weeks or 20 weeks post-injury. Histologic analyses and immunohistochemical staining (IHC) of the femoral head articular cartilage were performed, along with CT analysis to assess subchondral bone remodeling. We observed that mice receiving abductor injury exhibited significant OA severity with loss of Type II Collagen staining compared to sham control mice at 20 weeks post-surgery, comparable MMPI13 expression was observed between injury and sham groups. No significant differences in subchondral bone were found on CT after 20 weeks following injury. Our study suggests a link between abductor dysfunction and the development of hip OA, which are common pathomorphologies encountered in routine orthopaedic clinical practice. Further, this novel animal model may provide a valuable tool for future investigations into the pathogenesis and treatment of hip OA.

pathology↗