Control of Bone Resorption by Semaphorin 4D Is Dependent on Ovarian Function

Osteoporosis is one of the most common bone pathologies, which are characterized by a decrease in bone mass. It is well established that bone mass, which results from a balanced bone formation and bone resorption, is regulated by many hormonal, environmental and genetic factors. Here we report that the immune semaphorin 4D (Sema4D) is a novel factor controlling bone resorption. Sema4D-deficient primary osteoclasts showed impaired spreading, adhesion, migration and resorption due to altered ß3 integrin sub-unit downstream signaling. In apparent accordance with these in vitro results, Sema4D deletion in sexually mature female mice led to a high bone mass phenotype due to defective bone resorption by osteoclasts. Mutant males, however, displayed normal bone mass and the female osteopetrotic phenotype was only detected at the onset of sexual maturity, indicating that, in vivo, this intrinsic osteoclast defect might be overcome in these mice. Using bone marrow cross transplantation, we confirmed that Sema4D controls bone resorption through an indirect mechanism. In addition, we show that Sema4D −/− mice were less fertile than their WT littermates. A decrease in Gnrh1 hypothalamic expression and a reduced number of ovarian follicles can explain this attenuated fertility. Interestingly, ovariectomy abrogated the bone resorption phenotype in Sema4D −/− mice, providing the evidence that the observed high bone mass phenotype is strictly dependent on ovarian function. Altogether, this study reveals that, in vivo, Sema4D is an indirect regulator of bone resorption, which acts via its effect on reproductive function.骨质疏松症是最常见的骨骼疾病之一，其特征为骨量减少。现已明确，骨量由平衡的骨形成与骨吸收共同维持，并受多种激素、环境及遗传因素调控。本研究报道，免疫信号素4D（Sema4D）是一种全新的骨吸收调控因子。Sema4D缺陷的原代破骨细胞因β3整合素亚基下游信号通路异常，其铺展、黏附、迁移及骨吸收功能均受到损伤。与上述体外实验结果相符的是，性成熟雌性小鼠体内的Sema4D缺失会导致破骨细胞骨吸收功能缺陷，进而引发高骨量表型。但Sema4D敲除的雄性小鼠骨量却保持正常，且雌性小鼠的骨硬化表型仅在性成熟初期才可观测到，这提示在体条件下，该破骨细胞的内在缺陷可在小鼠体内得到代偿。通过骨髓交叉移植实验，我们证实Sema4D可通过间接机制调控骨吸收。此外，本研究发现Sema4D−/−小鼠的生育能力较其野生型（WT）同窝仔鼠有所下降，这可归因于下丘脑GnRH1表达降低以及卵巢卵泡数量减少。有趣的是，卵巢切除术可消除Sema4D−/−小鼠的骨吸收缺陷表型，证明其所观测到的高骨量表型严格依赖于卵巢功能。综上，本研究揭示，在体条件下Sema4D是一种间接的骨吸收调控因子，其通过影响生殖功能发挥调控作用。