Iwamoto M, Enomoto-Iwamoto M, Kurisu K
Department of Oral Anatomy & Developmental Biology, Osaka University Faculty of Dentistry, Suita, Japan.
Crit Rev Oral Biol Med. 1999;10(4):477-86. doi: 10.1177/10454411990100040401.
Recent advances in developmental and molecular biology during embryogenesis and organogenesis have provided new insights into the mechanism of bone formation. Members of the hedgehog gene family were initially characterized as patterning factors in embryonic development, but recently they have been shown to regulate skeletal formation in vertebrates. The amino terminal fragment of Sonic hedgehog (Shh-N), which is an active domain of Shh, has the ability to induce ectopic cartilage and bone formation in vivo. Shh-N stimulates chondrogenic differentiation in cultures of chondrogenic cell line cells in vitro and inhibits chondrogenesis in primary limb bud cells. These findings suggest that the regulation of chondrogenesis by hedgehog proteins depends on the cell populations being studied. Indian hedgehog (Ihh) is prominently expressed in developing cartilage. Ectopic expression of Ihh decreases type X collagen expression and induces the up-regulation of parathyroid hormone-related peptide (PTHrp) gene expression in perichondrium cells. A negative feedback loop consisting of Ihh and PTHrp, induced by Ihh, appears to regulate the rate of chondrocyte maturation. The direct actions of Shh and Ihh on stimulation of osteoblast differentiation are evidenced by the findings that these factors stimulate alkaline phosphatase activity in cultures of pluripotent mesenchymal cell line cells and osteoblastic cells and that these cells express putative receptors of hedgehog proteins. In conclusion, hedgehog proteins seem to be significantly involved in skeletal formation through multiple actions on chondrogenic mesenchymal cells, chondrocytes, and osteogenic cells.
胚胎发生和器官发生过程中发育生物学和分子生物学的最新进展为骨形成机制提供了新的见解。刺猬基因家族的成员最初被表征为胚胎发育中的模式形成因子，但最近已证明它们可调节脊椎动物的骨骼形成。音猬因子（Shh）的氨基末端片段（Shh-N）是Shh的活性结构域，具有在体内诱导异位软骨和骨形成的能力。Shh-N在体外软骨细胞系细胞培养物中刺激软骨生成分化，并在原代肢芽细胞中抑制软骨生成。这些发现表明，刺猬蛋白对软骨生成的调节取决于所研究的细胞群体。印度刺猬因子（Ihh）在发育中的软骨中显著表达。Ihh的异位表达降低了X型胶原蛋白的表达，并诱导软骨膜细胞中甲状旁腺激素相关肽（PTHrp）基因表达的上调。由Ihh诱导的由Ihh和PTHrp组成的负反馈环似乎调节软骨细胞成熟的速率。Shh和Ihh对成骨细胞分化的直接刺激作用由以下发现证明：这些因子在多能间充质细胞系细胞和成骨细胞培养物中刺激碱性磷酸酶活性，并且这些细胞表达刺猬蛋白的假定受体。总之，刺猬蛋白似乎通过对软骨生成间充质细胞、软骨细胞和成骨细胞的多种作用而显著参与骨骼形成。
