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Objective We aimed to characterize severity and occurrence of knee osteoarthritis (OA), and effects of age, sex, body weight, and reproductive status on population-level normal variation in this condition in the baboon, a natural model of human knee OA. Methods We visually inspected articular cartilage of distal right femora of 464 baboons (309 females, 155 males) and assigned an OA severity score (comparable to a modified Outerbridge score) from 1 = unaffected to 4 = advanced OA (eburnation). Presence/absence of osteophytes was recorded. We tested for significant effects of age, sex, weight, and, in females, reproductive status (pre-, peri-, or post-menopausal) on OA. When appropriate, analyses were repeated on an age-matched subset (153 of each sex). Results Knee OA was more frequent and severe in older animals (p < 0.0001), but significant age variation was apparent in each severity grade. Sex differences within the younger and older age groups suggest that males develop knee OA earlier, but females progress more quickly to advanced disease. There is a strong relationship between reproductive status and OA severity grade in females (p = 0.0005) with more severe OA in peri- and post-menopausal female baboons, as in humans. Conclusions Idiopathic knee OA is common in adult baboons. Occurrence and severity are influenced strongly by reproductive status in females, and by sex with regard to patterns of disease progression – providing an animal model to investigate sex-specific variation in OA susceptibility in which the environmental heterogeneity inherent in human populations is vastly reduced.

Intracortical microstructure influences crack propagation and arrest within bone cortex. Genetic variation in intracortical remodeling may contribute to mechanical integrity and, therefore, fracture risk. Our aim was to determine the degree to which normal population-level variation in intracortical microstructure is due to genetic variation. We examined right femurs from 101 baboons (74 females, 27 males; aged 7–33 years) from a single, extended pedigree to determine osteon number, osteon area (On.Ar), haversian canal area, osteon population density, percent osteonal bone (%On.B), wall thickness (W.Th), and cortical porosity (Ct.Po). Through evaluation of the covariance in intracortical properties between pairs of relatives, we quantified the contribution of additive genetic effects (heritability [h2]) to variation in these traits using a variance decomposition approach. Significant age and sex effects account for 9 % (Ct.Po) to 21 % (W.Th) of intracortical microstructural variation. After accounting for age and sex, significant genetic effects are evident for On.Ar (h2 = 0.79, p = 0.002), %On.B (h2 = 0.82, p = 0.003), and W.Th (h2 = 0.61, p = 0.013), indicating that 61–82 % of the residual variation (after accounting for age and sex effects) is due to additive genetic effects. This corresponds to 48–75 % of the total phenotypic variance. Our results demonstrate that normal, population-level variation in cortical microstructure is significantly influenced by genes. As a critical mediator of crack behavior in bone cortex, intracortical microstructural variation provides another mechanism through which genetic variation may affect fracture risk.

Osteogenic differentiation of mesenchymal stem cells (MSC) is important in the field of bone tissue engineering. The identification of biological factors that influence osteogenesis is vital for developing a broader understanding of how complex microenvironments play a role in differentiation. The aim of this study was to demonstrate that adipose-derived stem cell (ADSC) osteogenesis is enhanced through interaction with extracellular matrices (ECM) secreted by ADSC undergoing osteogenesis. ADSC were obtained from human patients following elective abdominoplasty. Cells were selected for plastic adherence, characterized, and induced to differentiate using osteogenic supplements (OS; dexamethasone, ascorbic acid, and beta-glycerol phosphate). Cells were removed at several time points during osteogenesis and the secreted ECM was isolated. Undifferentiated cells were re-seeded onto the cell secreted ECMs and induced to differentiate with OS. At several time points, cells cultured on ECMs or tissue culture plastic controls (i.e. uncoated surface) were collected and RNA isolated. QPCR and gene array analysis revealed enrichment of osteogenic markers and more rapid progression through osteogenic maturational phases in cells seeded onto ECM secreted at the midpoint in differentiation (ca. 15 days). Our results demonstrate that the cumulative deposition of ECM reaches a critical point at approximately 15 days, before which there appear to be no definitive osteogenic cues from the matrix, and after which, strong drivers of osteogenesis are present. The creation of microenvironments that contain essential morphogenic matrix signals is an important step towards methods of growing and differentiating MSC in a rapid effective manner, particularly for bone-related clinical applications.

Acetylated-Histone 3 (A-H3) level was increased upon treatment with all 4 HDIs, consistent with effective suppression of HDAC activity. The most effective specific HDI was MS275, which showed similar A-H3 levels to TSA, but exhibited some undesirable effects of pan-HDI. PCI increased A-H3 levels, though not as effective as MS275, but also reduced the negative effects of TSA, such as decreased COX-2 and MMP-3 expression under treatment with IL1b. Also, the additive effect of TSA and IL1b on the secretion of MMP3 was not observed in the case of PCI. Chondrocyte proliferation and survival was unaffected by the tested HDIs after 24 h of culture, with the exception of Droxinostat at concentration over 20 mm(decreased proliferation as shown by MTS assay and increased cell death as shown by Live/Dead assay). However, upon longer incubation (48 h), both TSA (200 nM) and Droxinostat reduced chondrocyte proliferation, while MS275, PCI and Tubostatin A increased it. Conclusions: The HDI, PCI, appears to be a promising candidate for reducing inflammatory and catabolic markers in chondrocytes exposed to pro-inflammatory cytokines. Further studies will investigate the effect of increasing PCI concentrations in two in vitro chondrocytebased OA models: (1) IL1b treatment; and (2) exposure to supraphysiological mechanical loading. In addition, MS275 could be a good alternative to pan-HDAC inhibitors, such as TSA, when longer exposure times are needed.