Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, MI 48109-1078, USA; Faculty of Budo and Sport Studies, Tenri University, Nara 6320071, Japan; Center for Excellence in Hip Disorders, Texas Scottish Rite Hospital for Children, Dallas, TX 75219, USA.
School of Dentistry, University of North Carolina, Chapel Hill, NC 27599, USA; College of Dentistry, University of Illinois at Chicago, Chicago, IL 60612, USA.
Bone. 2020 Sep;138:115513. doi: 10.1016/j.bone.2020.115513. Epub 2020 Jun 27.
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.
骨形态发生蛋白（BMPs）在 50 多年前被首次描述为具有强大的异位骨形成诱导作用，当它们被皮下给药时。临床前研究已经广泛研究了 BMPs 在体外的成骨特性和体内新骨形成。BMPs（BMP-2、BMP-7）已经在骨科中使用了超过 15 年。虽然 BMPs 的成骨功能已被广泛接受，但我们之前的研究表明，BMP 受体 I 型（BMPR1A）的功能丧失，一种 BMP-2 的有效受体，通过显著抑制小鼠的骨吸收，增加了净骨量，表明 BMP 信号在骨吸收中具有积极作用。BMPs 的生理作用（即成骨作用与破骨作用）在很大程度上仍然未知。本研究的目的是研究 BMP 信号在成年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 条件性和组成性激活 Smad 依赖性经典 BMP 信号。因为在 BMPR1A 功能丧失的小鼠研究中，小梁骨大量增加，我们假设增强的 BMP 信号会影响内源性小梁骨。在突变骨中，Smad 磷酸化增强至生理水平的三倍，而总体形态、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改变。有趣的是，我们发现；1）股骨骨形成和吸收标志物的表达增加，2）通过小梁骨组织形态计量学观察到成骨细胞和破骨细胞数量以及动态骨形成参数增加，3）骨结构表型适度，骨质量降低（即小梁骨连通性降低、直径增大但皮质骨厚度降低、骨机械强度降低），4）突变骨中 Smad 依赖性 BMPR1A 信号的下游靶标 SOST 的表达增加。这项研究具有临床意义，因为在生理窗口内获得 BMP 信号的功能不会增加骨量，同时改变了成骨细胞和破骨细胞功能的分子和细胞方面，正如预测的那样。这些发现有助于解释在临床环境中需要高剂量的 BMPs（即药理学水平）才能实质性地诱导骨形成，同时伴随着潜在的意外副作用（即骨吸收、炎症），这可能是由于更多类型的细胞暴露于高剂量的 BMPs 而不是成骨细胞谱系细胞。
