Inhibition of Ca²⁺/calmodulin-dependent protein kinase kinase 2 stimulates osteoblast formation and inhibits osteoclast differentiation.
Inhibition of Ca²⁺/calmodulin-dependent protein kinase kinase 2 stimulates osteoblast formation and inhibits osteoclast differentiation.
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DOI：
10.1002/jbmr.1890
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发表时间：
2013-07
影响因子：
6.2
通讯作者：
Sankar, Uma
中科院分区：
文献类型：
--
作者：
Cary, Rachel L.;Waddell, Seid;Racioppi, Luigi;Long, Fanxin;Novack, Deborah V.;Voor, Michael J.;Sankar, Uma
关键词：
骨重塑是一种生理过程，其特征是成骨细胞（OB）形成骨和破骨细胞（OC）吸收预先存在的骨基质，对于维持成年人的健康骨组织至关重要。这一重要过程的不平衡会导致包括骨质疏松症在内的病理状况。由于骨质疏松症最初无症状，通常只有在患者出现明显的骨质流失或骨折后才被发现。因此，刺激骨生成的合成代谢疗法具有很高的临床需求。在这里，我们将 Ca2+/钙调蛋白 (CaM) 依赖性蛋白激酶激酶 2 (CaMKK2) 确定为此类治疗的潜在靶标，因为它的抑制作用可增强 OB 分化和骨生长，并抑制 OC 分化。 CaMKK2 缺失的小鼠的长骨中具有更高的骨小梁质量，并且 OB 明显增多，多核 OC 更少。尽管 Camkk2−/− MSC 产生的 OB 数量明显较多，但来自 Camkk2−/− 小鼠的骨髓细胞在体外产生的多核 OC 较少。 CaMKK2 的选择性细胞渗透性药物抑制剂 STO-609 对其进行急性抑制也会导致 OB 增加和 OC 形成减少。此外，我们发现磷酸化蛋白激酶 A (PKA) 和环磷酸腺苷 (cAMP) 反应元件结合蛋白 (pCREB) 的 Ser133 磷酸化形式在 CaMKK2 缺陷的 OB 祖细胞中显着升高。另一方面，OC 祖细胞中 CaMKK2 的基因消除或其药理学抑制会导致 pCREB 减少，并显着降低其转录靶标、活化 T 细胞核因子 c1 (NFATc1) 的水平。此外，体内施用 STO-609 会导致 OB 增加和 OC 减少，从而显着保护成年小鼠免受卵巢切除 (OVX) 诱导的骨质疏松症。总的来说，我们的研究结果揭示了 CaMKK2 在骨重塑中的新功能，并强调了其治疗抑制作为一种有价值的骨合成代谢策略的潜力，该策略还可以在骨质疏松症治疗中抑制 OC 分化。
Bone remodeling, a physiological process characterized by bone formation by osteoblasts (OB) and resorption of pre-existing bone matrix by osteoclasts (OC), is vital for the maintenance of healthy bone tissue in adult humans. Imbalances in this vital process result in pathological conditions including osteoporosis. Owing to its initial asymptomatic nature, osteoporosis is often detected only after the patient has sustained significant bone loss or a fracture. Hence, anabolic therapeutics that stimulates bone accrual is in high clinical demand. Here we identify Ca2+/calmodulin (CaM)-dependent protein kinase kinase 2 (CaMKK2) as a potential target for such therapeutics, as its inhibition enhances OB differentiation and bone growth and suppresses OC differentiation. Mice null for CaMKK2 possess higher trabecular bone mass in their long bones, along with significantly more OBs and fewer multinuclear OCs. Whereas Camkk2−/− MSCs yield significantly higher numbers of OBs, bone marrow cells from Camkk2−/− mice produce fewer multinuclear OCs, in vitro. Acute inhibition of CaMKK2 by its selective, cell-permeable pharmacological inhibitor STO-609 also results in increased OB and diminished OC formation. Further, we find phospho-protein kinase A (PKA) and Ser133 phosphorylated form of cyclic adenosine monophosphate (cAMP) response element binding protein (pCREB) to be markedly elevated in OB progenitors deficient in CaMKK2. On the other hand, genetic ablation of CaMKK2 or its pharmacological inhibition in OC progenitors results in reduced pCREB as well as significantly reduced levels of its transcriptional target, nuclear factor of activated T cells c1 (NFATc1). Moreover, in vivo administration of STO-609 results in increased OBs and diminished OCs, conferring significant protection from ovariectomy (OVX)-induced osteoporosis in adult mice. Overall, our findings reveal a novel function for CaMKK2 in bone remodeling and highlight the potential for its therapeutic inhibition as a valuable bone anabolic strategy that also inhibits OC differentiation in the treatment of osteoporosis.
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影响因子：
6.2
作者：
Sankar, U;Patel, K;Ostrowski, MC
通讯作者：
Ostrowski, MC
影响因子：
4.8
作者：
Racioppi, Luigi;Noeldner, Pamela K.;Means, Anthony R.
通讯作者：
Means, Anthony R.
影响因子：
4.8
作者：
Tyson, DR;Swarthout, JT;Partridge, NC
通讯作者：
Partridge, NC
影响因子：
82.9
作者：
Nakashima, Tomoki;Hayashi, Mikihito;Takayanagi, Hiroshi
通讯作者：
Takayanagi, Hiroshi
影响因子：
4.8
作者：
Tokumitsu, H;Inuzuka, H;Kobayashi, R
通讯作者：
Kobayashi, R