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Clinical efforts to repair cartilage defects delivering cells or engineered cartilage implants into the lesions have met with limited success. This study used a critical-size chondral defect model in immunocompromised rat xiphoid cartilage to test whether endogenous chondrogenesis could be achieved using human bone matrix scaffolds to deliver human cartilage particles and/or a variant isoform of fibroblast growth factor-2 (FGF2-variant). Seventy-two male athymic RNU rats were enrolled in this study with eight rats per experimental group. Decellularized and demineralized human bone matrix scaffolds loaded with human articular cartilage particles or heat-inactivated cartilage particles were combined with different doses of the FGF2-variant. Scaffolds were implanted into 3-mm-diameter critical-size defects prepared using a biopsy punch through the center of the xiphoid. The samples were evaluated 28 days postsurgery using X-ray, equilibrium partitioning of ionic contrast microcomputed tomography, and safranin O-stained histological sagittal sections. Scaffolds containing cartilage particles plus the FGF2-variant induced dose-dependent increases in the formation of neocartilage (p<0.05), which was distributed homogeneously throughout the defects in comparison to scaffolds containing only the FGF2-variant. These effects were less pronounced when scaffolds with heat-inactivated cartilage particles were used. These results demonstrate that endogenous repair of chondral defects can be achieved in the absence of exogenous cells or bone marrow, suggesting that a similar approach may be successful for treating chondral lesions clinically.

Objective To assess temporal changes in cartilage and bone morphology, reactive oxygen species (ROS), and vascularization in rats with monosodium iodoacetate (MIA)-induced osteoarthritis (OA), using advanced imaging methodologies. Methods Right knees of 8-week-old male Wistar rats were injected with 1 mg MIA in 50 μl saline and left knees were injected with 50 μl saline as controls. After 1, 2, and 3 weeks (n = 5 at each time point), changes in cartilage morphology and composition were quantified using equilibrium partitioning of an ionic contrast agent microfocal computed tomography (μCT), and changes in subchondral and trabecular bone were assessed by standard μCT. ROS were characterized by in vivo fluorescence imaging at 1, 11, and 21 days (n = 5 at each time point). Three weeks following fluorescence imaging, alterations in knee joint vascularity were quantified with μCT after perfusion of a vascular contrast agent. Results Femoral cartilage volume, thickness, and proteoglycan content were significantly decreased in MIA-injected knees compared with control knees, accompanied by loss of trabecular bone and erosion of subchondral bone surface. ROS quantities were significantly increased 1 day after MIA injection and subsequently decreased gradually, having returned to normal by 21 days. Vascularity in whole knees and distal femora was significantly increased at 21 days after MIA injection. Conclusion Contrast-enhanced μCT and fluorescence imaging were combined to characterize articular cartilage, subchondral bone, vascularization, and ROS, providing unprecedented 3-dimensional joint imaging and quantification in multiple tissues during OA progression. These advanced imaging techniques have the potential to become standardized methods for comprehensive evaluation of articular joint degeneration and evaluation of therapeutic efficacy. [ABSTRACT FROM AUTHOR]

Bone morphogenetic protein 2 ( BMP2 ) in chromosomal region 20p12 belongs to a gene superfamily encoding TGF-β-signaling proteins involved in bone and cartilage biology. Monoallelic deletions of 20p12 are variably associated with cleft palate, short stature, and developmental delay. Here, we report a cranioskeletal phenotype due to monoallelic truncating and frameshift BMP2 variants and deletions in 12 individuals from eight unrelated families that share features of short stature, a recognizable craniofacial gestalt, skeletal anomalies, and congenital heart disease. De novo occurrence and autosomal-dominant inheritance of variants, including paternal mosaicism in two affected sisters who inherited a BMP2 splice-altering variant, were observed across all reported families. Additionally, we observed similarity to the human phenotype of short stature and skeletal anomalies in a heterozygous Bmp2 -knockout mouse model, suggesting that haploinsufficiency of BMP2 could be the primary phenotypic determinant in individuals with predicted truncating variants and deletions encompassing BMP2 . These findings demonstrate the important role of BMP2 in human craniofacial, skeletal, and cardiac development and confirm that individuals heterozygous for BMP2 truncating sequence variants or deletions display a consistent distinct phenotype characterized by short stature and skeletal and cardiac anomalies without neurological deficits. [ABSTRACT FROM AUTHOR]