Abstract
Pseudoachondroplasia (PSACH), a severe dwarfing condition characterized by impaired skeletal growth and early joint degeneration, results from mutations in cartilage oligomeric matrix protein (COMP). These mutations disrupt normal protein folding, leading to the accumulation of misfolded COMP in chondrocytes. The MT-COMP mouse is a murine model of PSACH that expresses D469del human COMP in response to doxycycline and replicates the PSACH chondrocyte and clinical pathology. The basis for the mutant-COMP pathology involves endoplasmic reticulum (ER) stress signaling through the PERK/eIF2α/CHOP pathway. C/EBP homologous protein (CHOP), in conjunction with a TNFα inflammatory process, upregulates mTORC1, hindering autophagy clearance of mutant COMP protein. Life-long joint pain/degeneration diminishes quality of life, and treatments other than joint replacements are urgently needed. To assess whether molecules that reduce CHOP activity should be considered as a potential treatment for PSACH, we evaluated MT-COMP mice with 50% CHOP (MT-COMP/CHOP+/-), antisense oligonucleotide (ASO)-mediated CHOP knockdown, and complete CHOP ablation (MT-COMP/CHOP-/-). While earlier studies demonstrated that loss of CHOP in MT-COMP mice reduced intracellular retention, inflammation, and growth plate chondrocyte death, we now show that it did not normalize limb growth. ASO treatment reduced CHOP mRNA by approximately 60%, as measured by RT-qPCR, but did not improve limb length similar to MT-COMP/CHOP+/-. Interestingly, both 50% genetic reduction and complete loss of CHOP alleviated pain, while total ablation of CHOP in MT-COMP mice was necessary to preserve joint health. These results indicate that (1) CHOP reduction therapy is not an effective strategy for improving limb length and (2) pain and chondrocyte pathology are more responsive to intervention than the prevention of joint damage.