Targeting macrophagic SHP2 for ameliorating osteoarthritis via TLR signaling

Osteoarthritis (OA), in which M1 macrophage polarization in the synovium exacerbates disease progression, is a major cause of cartilage degeneration and functional disabilities. Therapeutic strategies of OA designed to interfere with the polarization of macrophages have rarely been reported. Here, we report that SHP099, as an allosteric inhibitor of src-homology 2-containing protein tyrosine phosphatase 2 (SHP2), attenuated osteoarthritis progression by inhibiting M1 macrophage polarization. We demonstrated that M1 macrophage polarization was accompanied by the overexpression of SHP2 in the synovial tissues of OA patients and OA model mice. Compared to wild-type (WT) mice, myeloid lineage conditional Shp2 knockout (cKO) mice showed decreased M1 macrophage polarization and attenuated severity of synovitis, an elevated expression of cartilage phenotype protein collagen II (COL2), and a decreased expression of cartilage degradation markers collagen X (COL10) and matrix metalloproteinase 3 (MMP3) in OA cartilage. Further mechanistic analysis showed thatSHP099 inhibited lipopolysaccharide (LPS)-induced Toll-like receptor (TLR) signaling mediated by nuclear factor kappa B (NF-κB) and PI3K-AKT signaling. Moreover, intra-articular injection of SHP099 also significantly attenuated OA progression, including joint synovitis and cartilage damage. These results indicated that allosteric inhibition of SHP2 might be a promising therapeutic strategy for the treatment of OA.

Replication of Caucasian Loci Associated with Osteoporosis-related Traits in East Asians

BACKGROUND: Most reported genome-wide association studies (GWAS) seeking to identify the loci of osteoporosis-related traits have involved Caucasian populations. We aimed to identify the single nucleotide polymorphisms (SNPs) of osteoporosis-related traits among East Asian populations from the bone mineral density (BMD)-related loci of an earlier GWAS meta-analysis. METHODS: A total of 95 SNPs, identified at the discovery stage of the largest GWAS meta-analysis of BMD, were tested to determine associations with osteoporosis-related traits (BMD, osteoporosis, or fracture) in Korean subjects (n=1,269). The identified SNPs of osteoporosis-related traits in Korean subjects were included in the replication analysis using Chinese (n=2,327) and Japanese (n=768) cohorts. RESULTS: A total of 17 SNPs were associated with low BMD in Korean subjects. Specifically, 9, 6, 9, and 5 SNPs were associated with the presence of osteoporosis, non-vertebral fractures, vertebral fractures, and any fracture, respectively. Collectively, 35 of the 95 SNPs (36.8%) were associated with one or more osteoporosis-related trait in Korean subjects. Of the 35 SNPs, 19 SNPs (54.3%) were also associated with one or more osteoporosis-related traits in East Asian populations. Twelve SNPs were associated with low BMD in the Chinese and Japanese cohorts. Specifically, 3, 4, and 2 SNPs were associated with the presence of hip fractures, vertebral fractures, and any fracture, respectively. CONCLUSIONS: Our results identified the common SNPs of osteoporosis-related traits in both Caucasian and East Asian populations. These SNPs should be further investigated to assess whether they are true genetic markers of osteoporosis.

Genetics of Ossification of the Posterior Longitudinal Ligament of the Spine: A Mini Review

Ossification of the posterior longitudinal ligament of the spine (OPLL) is a common disease in aging populations and sometimes results in serious neurological problems due to compression of the spinal cord and nerve roots. OPLL is a multi-factorial (polygenic) disease controlled by genetic and environmental factors. Studies searching for the genetic component of OPLL, using linkage and association analyses, are in progress and several susceptibility genes have been reported. This paper reviews the recent progress in the genetic study of OPLL and comments on its future task.

A Short History of the Genome-Wide Association Study: Where We Were and Where We Are Going

Recent rapid advances in genetic research are ushering us into the genome sequence era, where an individual's genome information is utilized for clinical practice. The most spectacular results of the human genome study have been provided by genome-wide association studies (GWASs). This is a review of the history of GWASs as related to my work. Further efforts are necessary to make full use of its potential power to medicine.