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.

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Intraocular inflammation (uveitis) was produced in rabbits by intravenous or subcutaneous treatment with N-acetylmuramyl-L-alanyl-D-isoglutamine and several of its synthetic analogs at doses of -0.2 mg/kg in saline. A dose-dependent increase in permeability of the ocular blood-aqueous barrier as measured by leakage of protein or fluoresceinated dextran from the serum into the eye was observed from 2 to 14 h after glycopeptide treatment. Peak response occurred at approximately 3 h postdose. The lowest dose found to produce maximal vascular leakage for the most active glycopeptide analogs was 1 mg/kg. The adjuvant-inactive L-L stereoisomer of N-acetylmuramyl-L-alanyl-D-isoglutamine was inactive, even at doses as high as 10 mg/kg. Analogs of N-acetylmuramyl-L-alanyl-D-isoglutamine which were homologous in the lactyl side chain were found to cause less uveitis. Chronic biweekly intravenous treatment of rabbits for 1 month with either N-acetyl-L-aaminobutyryl-D-isoglutamine or its lipophilic 6-O-stearoyl derivative at 1 mg/kg, but not with murabutide, resulted in leukocytic inflammatory lesions unique to the uveal tract of the eye. The uveitis was potentially reversible and occurred with decreased severity as long as 2 months after cessation of chronic treatment. Vascular leakage but not cellular infiltrate in the choroid could be modulated by pharmacologic means.

A linear correlation coefficient analysis, comparing in vivo anti-infective and reticuloendothelial stimulating activity of several different analogs of N-acetylmuramyl-L-alanyl-D-isoglutamine (muramyl dipeptide) suggests that the macrophage is an important target cell for these immunomodulating compounds. The increase in protection against infections of Candida albicans or Pseudomonas aeruginosa in normal or immunosuppressed mice after treatment with 18 different glycopeptides was found to correlate with the degree of clearance of colloidal carbon particles from the blood by the reticuloendothelial system after treatment with the same muramyl dipeptide analogs. The compound which gave the greatest protection in all four assays was N-acetylmuramyl-L-alpha-aminobutyryl-D-isoglutamine followed by N-acetyl-nor-muramyl-L-alanyl-D-isoglutamine. Both analogs were better than the parent muramyl dipeptide. Whether macrophage stimulation alone is responsible for the anti-infective properties of these compounds has not yet been determined.