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

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.