Developmental exposure to environmental factors has been linked to obesity risk later in life. Nuclear receptors are molecular sensors that play critical roles during development and, as such, are prime candidates to explain the developmental programming of disease risk by environmental chemicals. We have previously characterized the obesogen tributyltin (TBT), which activates the nuclear receptors peroxisome proliferator-activated receptor γ (PPARγ) and retinoid X receptor (RXR) to increase adiposity in mice exposed in utero. Mesenchymal stem cells (MSCs) from these mice are biased toward the adipose lineage at the expense of the osteoblast lineage, and MSCs exposed to TBT in vitro are shunted toward the adipose fate in a PPARγ-dependent fashion. To address where in the adipogenic cascade TBT acts, we developed an in vitro commitment assay that permitted us to distinguish early commitment to the adipose lineage from subsequent differentiation. TBT and RXR activators (rexinoids) had potent effects in committing MSCs to the adipose lineage, whereas the strong PPARγ activator rosiglitazone was inactive. We show that activation of RXR is sufficient for adipogenic commitment and that rexinoids act through RXR to alter the transcriptome in a manner favoring adipogenic commitment. RXR activation alters expression of enhancer of zeste homolog 2 (EZH2) and modifies genome-wide histone 3 lysine 27 trimethylation (H3K27me3) in promoting adipose commitment and programming subsequent differentiation. These data offer insights into the roles of RXR and EZH2 in MSC lineage specification and shed light on how endocrine-disrupting chemicals such as TBT can reprogram stem cell fate.

Early life exposure to endocrine-disrupting chemicals (EDCs) is an emerging risk factor for the development of obesity and diabetes later in life. We previously showed that prenatal exposure to the EDC tributyltin (TBT) results in increased adiposity in the offspring. These effects linger into adulthood and are propagated through successive generations. TBT activates two nuclear receptors, the peroxisome proliferator-activated receptor (PPAR) γ and its heterodimeric partner retinoid X receptor (RXR), that promote adipogenesis in vivo and in vitro. We recently employed a mesenchymal stem cell (MSC) model to show that TBT promotes adipose lineage commitment by activating RXR, not PPARγ. This led us to consider the functional consequences of PPARγ vs RXR activation in developing adipocytes. We used a transcriptomal approach to characterize genome-wide differences in MSCs differentiated with the PPARγ agonist rosiglitazone (ROSI) or TBT. Pathway analysis suggested functional deficits in TBT-treated cells. We then compared adipocytes differentiated with ROSI, TBT, or a pure RXR agonist IRX4204 (4204). Our data show that RXR activators ("rexinoids," 4204 and TBT) attenuate glucose uptake, blunt expression of the antidiabetic hormone adiponectin, and fail to downregulate proinflammatory and profibrotic transcripts, as does ROSI. Finally, 4204 and TBT treatment results in an inability to induce markers of adipocyte browning, in part due to sustained interferon signaling. Taken together, these data implicate rexinoids in the development of dysfunctional white adipose tissue that could potentially exacerbate obesity and/or diabetes risk in vivo. These data warrant further screening and characterization of EDCs that activate RXR.

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Background: Many procedures to reconstruct osteochondral defects of the elbow radiocapitellar (RC) joint lack versatility or durability or do not directly address the subchondral bone structure and function. Purpose/Hypothesis: To biomechanically characterize the RC joint contact area, force, pressure, and peak pressure before and after reconstruction of osteochondral defects using a novel hybrid reconstructive procedure. It was hypothesized that the procedure would restore the contact characteristics to the intact condition. Study Design: Controlled laboratory study. Methods: A total of 10 cadaveric elbows (mean age 67 ± 2.7 years) were dissected to isolate the humerus and radial head. RC contact area, contact force, mean contact pressure, and peak contact pressure were measured with the elbow at 45° of flexion and neutral forearm rotation at compressive loads of 25, 50, and 75 N. Osteochondral defects 8 and 11 mm in diameter were created at the center of the capitellum; the defects were then reconstructed with a titanium fenestrated threaded implant, countersunk in the subchondral bone, with an acellular dermal matrix allograft sutured in place on top of the implant. Five conditions (intact, 8-mm defect, 8-mm repair, 11-mm defect, and 11-mm repair) were tested and results were compared using repeated-measures analysis of variance. Results: Both 8- and 11-mm defects significantly increased RC mean contact pressure at all compressive loads ( P ≤ .008) and significantly increased peak contact pressure at compressive loads of 50 and 75 N ( P < .002) compared with the intact condition. Repair of the 8-mm defect significantly decreased RC mean contact pressure at 25- and 50-N loads ( P ≤ .009) and significantly decreased peak contact pressure at 50- and 75-N loads ( P ≤ .035) compared with the defect condition. Repair of the 11-mm defect decreased mean contact pressure significantly at all compressive loads ( P ≤ .001) and peak contact pressure at 50- and 75-N loads ( P < .044) compared with the defect condition. Conclusion: RC joint contact pressure was restored to intact conditions while avoiding increased peak contact pressure or edge loading after repairing osteochondral defects related to osteochondrosis with a novel hybrid reconstruction technique. Clinical Relevance: This hybrid procedure that addresses the entire osteochondral unit may provide a new treatment option for osteochondral defects.

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