Osteoblast apoptosis and bone turnover

With the discoveries of different death mechanisms, an emerging definition of apoptosis is the process of cell death associated with caspase activatio n or caspase-mediated cell death. This definition accepts that caspases rep resent the final common mechanistic pathway in apoptosis. Apoptosis may be triggered either by activation events that target mitochondria or endoplasm ic reticulum or by activation of cell surface "death receptors," for exampl e, those in the tumor necrosis factor (TNF) superfamily. In the postnatal a nd adult skeleton, apoptosis is integral to physiological bone turnover, re pair, and regeneration. The balance of osteoblast proliferation, differenti ation, and apoptosis determines the size of the osteoblast population at an y given time. Although apoptosis has been recorded in many studies of bone, the selective mechanisms invoked in the different models studied rarely ha ve been identified. This review offers a broad overview of the current gene ral concepts and controversies in apoptosis research and then considers spe cific examples of osteoblast apoptosis pertinent to skeletal development an d to the regulation of bone turnover. In reviewing selected work on interdi gital apoptosis in the developing skeleton, we discuss the putative roles o f the bone morphogenetic proteins (BMPs), Msx2, RAR-gamma, and death induce r obliterator 1 (DIO-1). In reviewing factors regulating apoptosis in the p ostnatal skeleton, we discuss roles of cytokines, growth factors, members o f the TNF pathway, and the extracellular matrix (ECM). Finally, the paradox ical effects of parathyroid hormone (PTH) on osteoblast apoptosis in vivo a re considered in the perspective of a recent hypothesis speculating that th is may be a key mechanism to explain the anabolic effects of the hormone. A n improved understanding of the apoptotic pathways and their functional out comes in bone turnover and fracture healing may facilitate development of m ore targeted therapeutics to control bone balance in patients with osteopor osis and other skeletal diseases.