Longitudinal bone growth occurs through endochondral ossification (EO), controlled by various signaling molecules. Retinoid X Receptor (RXR) is a nuclear receptor with important roles in cell death, development, and metabolism. However, little is known about its role in EO. In this study, the agonist SR11237 was used to evaluate RXR activation in EO. Rats given SR11237 from post-natal day 5 to post-natal day 15 were harvested for micro-computed tomography (microCT) scanning and histology. In parallel, newborn CD1 mouse tibiae were cultured with increasing concentrations of SR11237 for histological and whole-mount evaluation. RXR agonist-treated rats had shorter long bones than the controls and developed dysmorphia of the growth plate. Cells invading the calcified and dysmorphic growth plate appeared pre-hypertrophic in size and shape, in correspondence with p57 immunostaining. Additionally, SOX9-positive cells were found surrounding the calcified tissue. The epiphysis of SR11237-treated bones showed increased TRAP staining and additional TUNEL staining at the osteo-chondral junction. MicroCT revealed morphological disorganization in the long bones of the treated animals. This study suggests that stimulation of RXR causes irregular ossification, premature closure of the growth plate, and disrupted long bone growth in rodent models
Longitudinal bone growth occurs through endochondral ossification (EO), controlled by various signaling molecules. Retinoid X Receptor (RXR) is a nuclear receptor with important roles in cell death, development, and metabolism. However, little is known about its role in EO. In this study, the agonist SR11237 was used to evaluate RXR activation on EO.Rats given SR11237 from post-natal day 5 to 15 were harvested for micro-computed tomography scanning and histology. In parallel, newborn CD1 mouse tibiae were cultured with increasing concentrations of SR11237 for histological and whole mount evaluation.RXR agonist-treated rats were smaller than controls, and developed dysmorphia of the growth plate. Cells invading the calcified and dysmorphic growth plate appeared pre-hypertrophic in size and shape corresponding with P57 immunostaining. Additionally, SOX9 positive cells were found surrounding the calcified tissue. The epiphysis of SR11237 treated bones showed increased TRAP staining, and additional TUNEL staining at the osteo-chondral junction. MicroCT revealed morphological disorganization in the long bones of treated animals. Isolated mouse long bones treated with SR11237 grew significantly less than their DMSO controls.This study demonstrates that stimulation of the RXR receptor causes irregular ossification, premature closure of the growth plate, and disrupted long bone growth in rodent models. Longitudinal bone growth occurs through the process of endochondral ossification, in which a cartilaginous model first expands through the activity of chondrocytes, followed by replacement of cartilage by bone. Endochondral ossification begins with the condensation of mesenchymal cells that subsequently differentiate into chondrocytes, the primary cell type of cartilage. Chondrocytes begin expressing SRY (sex determining region Y)-box9 (SOX9) and synthesize a matrix comprised largely of type II collagen and the proteoglycan aggrecan [1]. These early cartilage cells have a distinct rounded shape, are scattered irregularly throughout the matrix, divide infrequently, and give rise to resting chondrocytes. Eventually, the resting cells begin to divide more rapidly, and enter the proliferative zone, although the driving force behind this shift in activity is not completely known [2]. While in the proliferating zone, cells appear flattened. Upon division, their daughter cells line up in columns along the longitudinal axis of the bone. The elongated shape and the longitudinal growth of endochondral bones are largely due to this spatial orientation [2], with chondrocyte proliferation as one key factor influencing longitudinal bone growth. Chondrocytes in the center of the cartilage eventually cease to proliferate and exit the cell cycle to become hypertrophic cells. Chondrocytes undergoing hypertrophy increase up to 20-fold in size [3], stop synthesizing SOX9, and begin expressing type X collagen instead of type II. Hypertrophic differentiation is driven by transcription factors such as runt-related transcription factor 2 (RUNX2) ...
Post-traumatic Osteoarthritis (PTOA) is a degenerative joint disease, leading to articular cartilage breakdown, osteophyte formation, and synovitis, caused by an initial joint trauma. Pro-inflammatory cytokines increase catabolic activity and may perpetuate inflammation following joint trauma. Interleukin-15 (IL-15), a pro-inflammatory cytokine, is increased in OA patients, although its roles in OA pathophysiology are not well characterized. IL-15 levels appear to correlate to self-reported pain levels, and polymorphisms in the IL-15 receptor alpha gene correlate to a 1.5-fold increase in OA symptoms. This could be due to IL-15 effects on the activity of proteinases, such as matrix metalloproteinases (MMP) -1, -3, and -7. Here we utilized Il15 deficient rats to examine the role of IL-15 in PTOA pathogenesis in an injury-induced model of OA. OA was surgically induced in Il15 deficient rats and control wild-type rats to compare PTOA progression. Semi-quantitative scoring of the articular cartilage, subchondral bone, osteophyte size, and synovium was performed by two blinded observers. Analyses of articular cartilage damage, subchondral bone damage, and osteophyte formation revealed no significant difference between Il15 deficient rats and wild-type rats following PTOA-induction. Similarly, synovitis scoring across 6 parameters found no significant difference between genetic variants. Overall, IL-15 does not appear to play a key role in the development of structural changes in this surgically-induced rat model of PTOA.
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