Regulation of osteoclast formation and function.

Abstract

The human skeleton is continuously remodeling during growth and in response to mechanical stress and hormonal regulation. The maintenance of normal bone mass during adult life depends on a precise balance between osteoblastic bone formation and osteoclastic bone destruction, implicating tight coupling between these two cellular activities. In various skeletal diseases associated with bone loss, including osteoporosis, hypercalcemia of malignancy, tumor metastases or Paget's disease, increased osteoclastic bone resorption exceeds formation resulting in low bone mass, skeletal fragility and increased risk of fracture. When considering therapeutic approaches to manage these diseases, inhibitors of bone resorption such as bisphosphonates or estrogen-like compounds have been proven effective. In this review, we will discuss new insights into osteoclast differentiation and activity which offer the potential new therapeutic targets for blocking bone resorption. Osteoclasts are multinucleated, terminally differentiated cells which degrade mineralized tissues during normal and pathological bone turnover [1±3]. The rate of bone resorption is tightly regulated through the control of osteoclast differentiation and activation. Osteoclast maturation involves the proliferation and homing to bone of the hemopoietic progenitors, which are shared with the monocyte-macrophage lineage. On the bone surface, osteoclast progenitors differentiate and fuse to form multinucleated cells, which migrate from one resorption site to the next. During resorption, osteoclasts attach ®rmly to the bone surface and form a tight sealing zone (or ``clear zone'') which encloses the resorption lacuna, frequently compared to a giant lysosome. Insertion of secretory vesicles into the bone-facing membrane forms a highly convoluted structure called the ``ruf ed border'', a characteristic feature of active osteoclasts. Because of the extensive literature on the regulation of osteoclast formation and function, this review will focus on the recent information regarding the regulation of osteoclast differentiation by the newly identi®ed cytokine RANKL/OPGL and the adhesion-dependent activation of these cells during the resorption cycle. Spontaneous mutations and many experimental gene deletions (knock-outs) in mice have identi®ed various stages of osteoclast development and function, as shown in Fig. 1. The myeloid and B lymphoid transcription factor PU.1, macrophage colony-stimulating factor (MCSF or CSF-1), c-fos, p50/p52 subunits of NF-kB, RANK and its ligands were shown to be essential for osteoclast differentiation [1,2]. Osteoclastic bone resorption was found to be regulated by many genes, including carbonic anhydrase type II, vacuolar ATPase, calcitonin receptor, tartrate resistant acid phosphatase (TRAP), c-Src, avb3 integrin and RANK/ligand [1,2,4].