Coupling Signals between the Osteoclast and Osteoblast: How are Messages Transmitted between These Temporary Visitors to the Bone Surface?

Natalie A. Sims; T. John Martin

摘要

Skeletal mass is regulated by two key activities: bone removal (resorption) by hematopoietic lineage osteoclasts and bone matrix formation by mesenchymal lineage osteoblasts. During adult life, these activities occur sequentially on the same surface: a process termed as remodeling. Tiny packets of bone are removed by osteoclasts and replaced by new bone matrix produced by osteoblasts. This continual renewal process allows repair of mechanical imperfections and calcium homeostasis. The group of cells responsible for remodeling is termed as the basic multicellular unit (BMU) ( 1 ). To maintain bone mass at the same level during adulthood, the bone formed in each BMU must replace precisely the amount removed by resorption within that BMU. This stimulation of osteoblast activity in response to resorption is termed “coupling” ( 2 ), and it has long been of interest to understand how these two distinct cell types, on the same bone surface but at different times, could be linked so their activities are equal. The BMU and coupling concepts originally included only osteoclasts and osteoblasts, but over recent years, as more cellular contributors to remodeling have been identified (such as T-cells, macrophages, osteocytes, and precursor populations of osteoblasts and osteoclasts), the number of cells in the BMU has expanded ( 3 – 5 ). So too, more signaling pathways within the BMU have been identified ( 6 , 7 ). All these signals converge on two cell types: the osteoclast and osteoblast, for only those cells are able of bone resorption and bone formation, respectively. Osteoclasts and osteoblasts are not present on the bone surface simultaneously; the BMU exists, in different forms, at the same location over approximately 6?months in human bone. Early studies using undecalcified bone histology and timed fluorochrome labeling identified that bone resorption in iliac crest trabecular BMUs of adult human bone takes approximately 3?weeks ( 8 ), the formation response 3–4?months ( 9 ), and between the two activities there is a poorly understood “reversal phase” ( 10 ) of approximately 5?weeks ( 8 ). In rodents, the duration of this sequence is compressed, but a time delay between resorption and formation still exists: in rat alveolar bone, the reversal phase lasts for approximately 3.5?days ( 11 ). These numbers vary also with site, skeletal health, and treatment ( 12 ) and in some conditions, including osteoporosis there is an increased duration, or even arrest, of the reversal phase ( 13 , 14 ). This review will explore mechanisms by which coupling signals may overcome the time delay between bone resorption and bone formation. The Main Classes of Coupling Factors There are four main classes of osteoclast-derived signals that may promote bone formation in the BMU: (1) matrix-derived signals released during bone resorption, (2) factors synthesized and secreted by the mature osteoclast, (3) factors expressed on the osteoclast cell membrane, and (4) topographical changes effected by the osteoclast on the bone surface. We have reviewed these different proposed signals extensively elsewhere ( 6 , 7 ), but will here focus on how each type of signal might influence bone formation after the reversal phase. As it has been noted in economics, there tends to be a proliferation of putative factors that determine process outcomes until they resemble a “zoo of factors,” with only a proportion of them being reliably reproduced in later research ( 15 , 16 ). Since many coupling factors have only been identified in the past 10?years, most require validation by independent groups of researchers, working in multiple systems. This is particularly true of those factors identified in co-culture studies that disregard the time delay between bone resorption and formation. Matrix-derived factors The bone matrix contains a store of latent growth factors, including transforming growth factor β (TGF-β), bone morphogenetic protein 2 (BMP-2), platelet-derived growth factor (PDGF), and the insulin-like growth factors (IGFs) ( 17 – 21 ). All are deposited by osteoblasts during matrix production then released by osteoclastic activity on the bone surface ( 20 ), as well as via plasminogen activators ( 22 , 23 ) and matrix-metalloproteinases ( 24 ). These factors, once released from the matrix, are unlikely to remain within the bone microenvironment for some 5–8?weeks during the reversal phase until they can influence mature osteoblasts upon their arrival at the bone surface. Rather, their main influences would be to stimulate osteoblast progenitors, including their recruitment ( 25 – 27 ), migration ( 26 , 28 – 30 ), and differentiation ( 29 , 31 , 32 ). Osteoclast-secreted factors Osteoclasts also secrete products to promote osteoblast precursor recruitment and differentiation and thereby promote bone formation in the BMU ( 3 ). Many such “osteoclast-derived coupling factors” have been identified, and some were validated by studies of genetically alter

机译：骨骼质量受两个关键活动调节：造血谱系破骨细胞的去除骨（再吸收）和间质谱系成骨细胞的骨基质形成。在成年期间，这些活动顺序地在同一表面上发生：称为重塑的过程。破骨细胞去除了微小的骨块，并由成骨细胞产生的新骨基质代替。这种持续的更新过程可以修复机械缺陷和钙稳态。负责重塑的细胞群称为基本多细胞单位（BMU）（1）。为了在成年期间将骨量保持在相同水平，每个BMU中形成的骨骼必须精确地替代通过该BMU中的吸收而去除的骨量。这种响应吸收而刺激成骨细胞活性的过程称为“耦合”（2），了解如何将这两种不同的细胞类型（在同一骨表面但在不同时间）如何关联起来一直很有意义，相等。 BMU和耦合概念最初仅包括破骨细胞和成骨细胞，但是近年来，随着更多的细胞重构因素被发现（例如T细胞，巨噬细胞，骨细胞以及成骨细胞和破骨细胞的前体种群），细胞数量BMU中的扩展（3 – 5）。因此，在BMU中也发现了更多的信号通路（6、7）。所有这些信号都集中在两种细胞类型上：破骨细胞和成骨细胞，因为只有那些细胞能够分别进行骨吸收和骨形成。破骨细胞和成骨细胞不能同时存在于骨表面。 BMU以不同的形式存在于人体骨骼中大约6个月以上的相同位置。早期使用未脱钙的骨组织学和定时荧光标记的研究表明，成年人类骨骼骨小梁BMU的骨吸收需要大约3周（8周），形成反应需要3-4周（9个月），并且在这两种活动之间大约5周（8）的“逆转阶段”（10）尚不为人所知。在啮齿动物中，该序列的持续时间被压缩，但在吸收和形成之间仍然存在时间延迟：在大鼠牙槽骨中，逆转阶段持续约3.5天（11）。这些数字也随部位，骨骼健康和治疗的不同而有所变化（12），在某些情况下，包括骨质疏松症，逆转阶段的持续时间延长，甚至停滞（13、14）。这篇综述将探讨耦合信号可以克服骨吸收和骨形成之间的时间延迟的机制。耦合因子的主要类别破骨细胞衍生的信号有四种主要类别，它们可能会促进BMU中的骨形成：（1）骨吸收期间释放的基质衍生信号;（2）成熟破骨细胞合成和分泌的因子，（ 3）在破骨细胞细胞膜上表达的因子，以及（4）破骨细胞在骨表面上影响的地形变化。我们已经在其他地方（6，7）广泛地审查了这些不同的提议信号，但这里将集中讨论每种信号在反转阶段后如何影响骨形成。正如经济学中已经指出的那样，在确定过程结果之前，趋于普遍存在推定因素，这些结果类似于“因素的偶像”，只有一部分能在以后的研究中可靠地再现（15、16）。由于许多耦合因子仅在过去的10年中才被发现，因此大多数都需要由在多个系统中工作的独立研究人员小组进行验证。在共培养研究中发现的那些忽略骨吸收和形成之间的时间延迟的因素尤其如此。基质衍生因子骨基质包含潜在的生长因子，包括转化生长因子β（TGF-β），骨形态发生蛋白2（BMP-2），血小板衍生生长因子（PDGF）和胰岛素样生长因子（IGFs）（17 – 21）。所有这些都在基质产生过程中由成骨细胞沉积，然后通过破骨活性释放在骨表面上（20），以及通过纤溶酶原激活剂（22、23）和基质金属蛋白酶（24）释放。这些因素一旦从基质中释放出来，在反转阶段不太可能在骨骼微环境中保留约5-8周，直到它们影响成熟的成骨细胞到达骨表面为止。相反，它们的主要影响将是刺激成骨细胞祖细胞，包括其募集（25-27），迁移（26、28-30）和分化（29、31、32）。破骨细胞分泌的因子破骨细胞还分泌产物以促进成骨细胞前体的募集和分化，从而促进BMU中的骨形成（3）。已经确定了许多这样的“破骨细胞衍生的偶联因子”，并且一些通过遗传变异研究得到了验证。

Coupling Signals between the Osteoclast and Osteoblast: How are Messages Transmitted between These Temporary Visitors to the Bone Surface?

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