Summary:Bone marrow contains a population of rare progenitor cells capable of differentiating into bone, cartilage. tendon, and other connective tissues. These cells. referred to as mesenchymal stem cells, can be purified and culture-expanded from animals and humans and have been shown to regencrate functional tissue when delivered to the site of musculoskeletal defects in experimental animal$. To test the ability of purified human mesenchymal stem cells to heal a clinically significant bone defect, mesenchymal stem cells isolated from normal human bone marrow were culture-expanded, loaded onto a ceramic carrier, and implanted into critical-sized segmental defects in the femurs of adult athymic rats. For comparison, cell-free ceramics were implanted in the contralateral limb. The animals were euthanized at 4,8, or 12 weeks, and healing bone defects were compared by high-resolution radiography, immunoliistochemistry. quantitative histomorphometry. and biomechanical testing. In mesenchymal stem cell-loaded samples, radiographic and histologic evidence of new bone was apparent by 8 weeks and histoniorphometry demonstrated increasing bone formation through 12 weeks. Biomechanical evaluation confirmed that femurs implanted with mesenchymal stem cell-loaded ceramics were significantly stronger than those that received cell-lree ceramics. These studies demonstrate that human mesenchymal stern cells can regenerate bone in a clinically significant osscous defect and may therefore provide an alternative to autogcnous bone grafts.

The development of osteoporosis involves the interaction of multiple environmental and genetic factors. Through combined genetic and genomic approaches, we identified the lipoxygenase gene Alox15 as a negative regulator of peak bone mineral density in mice. Crossbreeding experiments with Alox15 knockout mice confirmed that 12/15-lipoxygenase plays a role in skeletal development. Pharmacologic inhibitors of this enzyme improved bone density and strength in two rodent models of osteoporosis. These results suggest that drugs targeting the 12/15-lipoxygenase pathway merit investigation as a therapy for osteoporosis.

This study examined the effect of 2 yr of treatment with the aminobisphosphonate alendronate (ALN) (0.05 or 0.25 mg/ kg i.v. ALN every 2 wk) on estrogen deficiency bone loss and bone strength changes in ovariectomized (OVX) baboons (n = 7 per group) and the ALN mode of action at the tissue level. Biochemical markers of bone turnover increased in OVX animals and were maintained by ALN treatment at non-OVX levels (low dose) or below (high dose). 2 yr of treatment produced no cumulative effects on bone turnover markers. Histomorphometry showed a marked increase in cancellous bone remodeling in OVX animals. Activation frequency increased from 0.48 to 0.86 per yr (L5 vertebra), and the osteoid surfaces from 9 to 13.5% (P < 0.05). No changes were observed in eroded and osteoclast surfaces. ALN treatment decreased activation frequency and indices of bone formation to control levels (low dose) or below (high dose), did not change indices of mineralization, and increased bone mineral density (BMD) in the lumbar vertebrae (L2-L4) by 15% at 0.25 mg/kg (P < 0.05), relative to vehicle-treated animals. The mean strength of cancellous bone (LA) increased by 44% (low ALN dose) and 100% (high dose), compared with vehicle. The strength of individual bones correlated with the square of the L2-L4 BMD (r = 0.91, P < 0.0034). In conclusion, ALN treatment reversed the effects of ovariectomy on cancellous bone turnover and increased bone mass and bone strength in baboons. (J. Clin. Invest. 1993. 92:2577-2586 Key words: osteoporosis * alendronate * histomorphometry-bone strength * bone mineral density

Adults with mental retardation in a group home received popcorn or coffee reinforcers for sorting plastic dinnerware. In Part 1 of the experiment, reinforcers were dispensed according to a variable-interval 60-s schedule for sorting dinnerware of one color and according to a variable-interval 240-s schedule for sorting dinnerware of a different color in successive components of a multiple schedule. Sorting rates were similar in baseline, but when a video program was shown concurrently, sorting of dinnerware was more resistant to distraction when correlated with a higher rate of reinforcement. In Part 2 of the experiment, popcorn or coffee reinforcers were contingent upon sorting both colors of dinnerware according to variable-interval 60-s schedules, but additional reinforcers were given independently of sorting according to a variable-time 30-s schedule during one dinnerware-color component. Baseline sorting rate was lower but resistance to distraction by the video program was greater in the component with additional variable-time reinforcers. These results demonstrate that resistance to distraction depends on the rate of reinforcers obtained in the presence of component stimuli but is independent of baseline response rates and response-reinforcer contingencies. Moreover, these results are similar to those obtained in laboratory studies with pigeons, demonstrating that the determination of resistance to change by stimulus-reinforcer relations is not confined to controlled laboratory settings or unique to the pigeon.