BMP 信号的生理与药理作用的争议：成骨细胞谱系中 BMP IA 型受体依赖性信号的组成性激活增强骨形成和吸收，不影响净骨量,Bone

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BMP 信号的生理与药理作用的争议：成骨细胞谱系中 BMP IA 型受体依赖性信号的组成性激活增强骨形成和吸收，不影响净骨量
Bone ( IF 3.5 ) Pub Date : 2020-09-01 , DOI: 10.1016/j.bone.2020.115513
Nobuhiro Kamiya ₁ , Phimon Atsawasuwan ₂ , Danese M Joiner ₃ , Erik I Waldorff ₃ , Steve Goldstein ₃ , Mitsuo Yamauchi ₄ , Yuji Mishina ₅

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50 多年前，骨形态发生蛋白 (BMP) 首次被描述为皮下给药时异位骨形成的有效诱导剂。临床前研究已经广泛检查了 BMP 在体外和体内新骨形成的骨诱导特性。BMP（BMP-2、BMP-7）已在骨科中使用超过 15 年。虽然 BMP 的成骨功能已被广泛接受，但我们之前的研究表明，BMP-2 的强效受体 BMP 受体 IA 型 (BMPR1A) 的功能丧失通过显着抑制小鼠的骨吸收来增加净骨量，表明BMP 信号在骨吸收中的积极作用。BMPs（即成骨与破骨）的生理作用仍然很大程度上未知。本研究的目的是研究 BMP 信号在成年期内源性长骨中的生理作用。为此，我们使用突变小鼠 (Col1CreER™:caBmpr1a) 在成骨细胞谱系细胞中通过 BMPR1A 有条件地和组成性地激活 Smad 依赖性经典 BMP 信号传导。因为在 BMPR1A 的功能丧失小鼠研究中骨小梁大量增加，我们假设增强的 BMP 信号传导会影响内源性骨小梁。在突变骨中，Smad 磷酸化在生理水平内增强了三倍，而由此产生的总体形态、体重、骨量/形状/长度、血清钙/磷水平、胶原交联模式和愈合能力均未发生变化。有趣的是，我们发现；1) 股骨中骨形成和再吸收标志物的表达增加，2) 成骨细胞和破骨细胞数量增加以及骨小梁组织形态学的动态骨形成参数，3) 适度的骨结构表型，骨质量降低（即骨小梁连接性降低，直径较大但皮质骨厚度减少，骨机械强度降低），和 4）增加 SOST 的表达，这是 Smad 依赖性 BMPR1A 信号传导的下游靶标，在突变骨中。这项研究具有临床意义，因为在生理窗口内 BMP 信号的功能获得不会增加骨量，但它会改变成骨细胞和破骨细胞功能的分子和细胞方面，如预测的那样。这些发现有助于解释高剂量的 BMP（即

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Controversy of physiological vs. pharmacological effects of BMP signaling: Constitutive activation of BMP type IA receptor-dependent signaling in osteoblast lineage enhances bone formation and resorption, not affecting net bone mass

Bone morphogenetic proteins (BMPs) were first described over 50 years ago as potent inducers of ectopic bone formation when administrated subcutaneously. Preclinical studies have extensively examined the osteoinductive properties of BMPs in vitro and new bone formation in vivo. BMPs (BMP-2, BMP-7) have been used in orthopedics over 15 years. While osteogenic function of BMPs has been widely accepted, our previous studies demonstrated that loss-of-function of BMP receptor type IA (BMPR1A), a potent receptor for BMP-2, increased net bone mass by significantly inhibiting bone resorption in mice, indicating a positive role of BMP signaling in bone resorption. The physiological role of BMPs (i.e. osteogenic vs. osteoclastogenic) is still largely unknown. The purpose of this study was to investigate the physiological role of BMP signaling in endogenous long bones during adult stages. For this purpose, we conditionally and constitutively activated the Smad-dependent canonical BMP signaling thorough BMPR1A in osteoblast lineage cells using the mutant mice (Col1CreER™:caBmpr1a). Because trabecular bones were largely increased in the loss-of-function mouse study for BMPR1A, we hypothesized that the augmented BMP signaling would affect endogenous trabecular bones. In the mutant bones, the Smad phosphorylation was enhanced within physiological level three-fold while the resulting gross morphology, bodyweights, bone mass/shape/length, serum calcium/phosphorus levels, collagen cross-link patterns, and healing capability were all unchanged. Interestingly, we found; 1) increased expressions of both bone formation and resorption markers in femoral bones, 2) increased osteoblast and osteoclast numbers together with dynamic bone formation parameters by trabecular bone histomorphometry, 3) modest bone architectural phenotype with reduced bone quality (i.e. reduced trabecular bone connectivity, larger diametric size but reduced cortical bone thickness, and reduced bone mechanical strength), and 4) increased expression of SOST, a downstream target of the Smad-dependent BMPR1A signaling, in the mutant bones. This study is clinically insightful because gain-of-function of BMP signaling within a physiological window does not increase bone mass while it alters molecular and cellular aspects of osteoblast and osteoclast functions as predicted. These findings help explain the high-doses of BMPs (i.e. pharmacological level) in clinical settings required to substantially induce a bone formation, concurrent with potential unexpected side effects (i.e. bone resorption, inflammation) presumably due to a broader population of cell-types exposed to the high-dose BMPs rather than osteoblastic lineage cells.

更新日期：2020-09-01

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