Chondrocyte hypertrophy followed by cartilage matrix degradation and vascular invasion, characterized by expression of type X collagen (COL10A1), matrix metalloproteinase-13 (MMP-13) and vascular endothelial growth factor (VEGF), respectively, are central steps of endochondral ossification during normal skeletal growth and osteoarthritis development. A COL10A1 promoter assay identified hypoxia-inducible factor-2alpha (HIF-2alpha, encoded by EPAS1) as the most potent transactivator of COL10A1. HIF-2alpha enhanced promoter activities of COL10A1, MMP13 and VEGFA through specific binding to the respective hypoxia-responsive elements. HIF-2alpha, independently of oxygen-dependent hydroxylation, was essential for endochondral ossification of cultured chondrocytes and embryonic skeletal growth in mice. HIF-2alpha expression was higher in osteoarthritic cartilages versus nondiseased cartilages of mice and humans. Epas1-heterozygous deficient mice showed resistance to osteoarthritis development, and a functional single nucleotide polymorphism (SNP) in the human EPAS1 gene was associated with knee osteoarthritis in a Japanese population. The EPAS1 promoter assay identified RELA, a nuclear factor-kappaB (NF-kappaB) family member, as a potent inducer of HIF-2alpha expression. Hence, HIF-2alpha is a central transactivator that targets several crucial genes for endochondral ossification and may represent a therapeutic target for osteoarthritis.

Musculoskeletal diseases, especially osteoarthritis (OA) and osteoporosis (OP), impair activities of daily life (ADL) and quality of life (QOL) in the elderly. Although preventive strategies for these diseases are urgently required in an aging society, epidemiological data on these diseases are scant. To clarify the prevalence of knee osteoarthritis (KOA), lumbar spondylosis (LS), and osteoporosis (OP) in Japan, and estimate the number of people with these diseases, we started a large-scale population-based cohort study entitled research on osteoarthritis/osteoporosis against disability (ROAD) in 2005. This study involved the collection of clinical information from three cohorts composed of participants located in urban, mountainous, and coastal areas. KOA and LS were radiographically defined as a grade of > or =2 by the Kellgren-Lawrence scale; OP was defined by the criteria of the Japanese Society for Bone and Mineral Research. The 3,040 participants in total were divided into six groups based on their age: < or =39, 40-49, 50-59, 60-69, 70-79, and > or =80 years. The prevalence of KOA in the age groups < or =39, 40-49, 50-59, 60-69, 70-79, and > or =80 years 0, 9.1, 24.3, 35.2, 48.2, and 51.6%, respectively, in men, and the prevalence in women of the same age groups was 3.2, 11.4, 30.3, 57.1, 71.9, and 80.7%, respectively. With respect to the age groups, the prevalence of LS was 14.3, 45.5, 72.9, 74.6, 85.3, and 90.1% in men, and 9.7, 28.6, 41.7, 55.4, 75.1, and 78.2% in women, respectively. Data of the prevalence of OP at the lumbar spine and femoral neck were also obtained. The estimated number of patients with KOA, LS, and L2-L4 and femoral neck OP in Japan was approximately 25, 38, 6.4, and 11 million, respectively. In summary, we estimated the prevalence of OA and OP, and the number of people affected with these diseases in Japan. The ROAD study will elucidate epidemiological evidence concerning determinants of bone and joint disease.

Based on the fact that aging is associated with a reciprocal decrease of osteogenesis and an increase of adipogenesis in bone marrow and that osteoblasts and adipocytes share a common progenitor, this study investigated the role of PPARγ γ, a key regulator of adipocyte differentiation, in bone metabolism. Homozygous PPARγ γ-deficient ES cells failed to differentiate into adipocytes, but spontaneously differentiated into osteoblasts, and these were restored by reintroduction of the PPARγ γ gene. Heterozygous PPARγ γ-deficient mice exhibited high bone mass with increased osteoblastogenesis, but normal osteoblast and osteoclast functions, and this effect was not mediated by insulin or leptin. The osteogenic effect of PPARγ γ haploinsufficiency became prominent with aging but was not changed upon ovariectomy. The PPARγ γ haploinsufficiency was confirmed to enhance osteoblastogenesis in the bone marrow cell culture but did not affect the cultures of differentiated osteoblasts or osteoclast-lineage cells. This study demonstrates a PPARγ γ-dependent regulation of bone metabolism in vivo, in that PPARγ γ insufficiency increases bone mass by stimulating osteoblastogenesis from bone marrow progenitors.Nonstandard abbreviations used: alkaline phosphatase (ALP); bone morphogenetic protein-2 (BMP-2); bone volume (BV); CCAAT enhancer-binding proteins (C/EBPs); computed tomography (CT); LDL receptor-related protein 5 (LRP5); leukemia inhibitory factor (LIF); M-CSF-dependent bone marrow macrophage (M-BMMφ); receptor activator of nuclear factor κB ligand (RANKL); ovariectomy (OVX); PPAR responsive element (PPRE); tartrate-resistant acid phosphatase (TRAP); tissue volume (TV); type I collagen α1 chain (COL1A1).

Based on the fact that aging is associated with a reciprocal decrease of osteogenesis and an increase of adipogenesis in bone marrow and that osteoblasts and adipocytes share a common progenitor, this study investigated the role of PPARγ γ, a key regulator of adipocyte differentiation, in bone metabolism. Homozygous PPARγ γ-deficient ES cells failed to differentiate into adipocytes, but spontaneously differentiated into osteoblasts, and these were restored by reintroduction of the PPARγ γ gene. Heterozygous PPARγ γ-deficient mice exhibited high bone mass with increased osteoblastogenesis, but normal osteoblast and osteoclast functions, and this effect was not mediated by insulin or leptin. The osteogenic effect of PPARγ γ haploinsufficiency became prominent with aging but was not changed upon ovariectomy. The PPARγ γ haploinsufficiency was confirmed to enhance osteoblastogenesis in the bone marrow cell culture but did not affect the cultures of differentiated osteoblasts or osteoclast-lineage cells. This study demonstrates a PPARγ γ-dependent regulation of bone metabolism in vivo, in that PPARγ γ insufficiency increases bone mass by stimulating osteoblastogenesis from bone marrow progenitors.Nonstandard abbreviations used: alkaline phosphatase (ALP); bone morphogenetic protein-2 (BMP-2); bone volume (BV); CCAAT enhancer-binding proteins (C/EBPs); computed tomography (CT); LDL receptor-related protein 5 (LRP5); leukemia inhibitory factor (LIF); M-CSF-dependent bone marrow macrophage (M-BMMφ); receptor activator of nuclear factor κB ligand (RANKL); ovariectomy (OVX); PPAR responsive element (PPRE); tartrate-resistant acid phosphatase (TRAP); tissue volume (TV); type I collagen α1 chain (COL1A1).

The present cross-sectional study revealed a high prevalence of radiographic knee OA in the Japanese elderly. Knee pain was strongly associated with JSN especially in men, while women tended to have knee pain even without radiographic OA.