With the discoveries of different death mechanisms, an emerging definition of apoptosis is the process of cell death associated with caspase activation or caspase-mediated cell death. This definition accepts that caspases represent the final common mechanistic pathway in apoptosis. Apoptosis may be triggered either by activation events that target mitochondria or endoplasmic reticulum or by activation of cell surface "death receptors," for example, those in the tumor necrosis factor (TNF) superfamily. In the postnatal and adult skeleton, apoptosis is integral to physiological bone turnover, repair, and regeneration. The balance of osteoblast proliferation, differentiation, and apoptosis determines the size of the osteoblast population at any given time. Although apoptosis has been recorded in many studies of bone, the selective mechanisms invoked in the different models studied rarely have been identified. This review offers a broad overview of the current general concepts and controversies in apoptosis research and then considers specific examples of osteoblast apoptosis pertinent to skeletal development and to the regulation of bone turnover. In reviewing selected work on interdigital apoptosis in the developing skeleton, we discuss the putative roles of the bone morphogenetic proteins (BMPs), Msx2, RAR-␥, and death inducer obliterator 1 (DIO-1). In reviewing factors regulating apoptosis in the postnatal skeleton, we discuss roles of cytokines, growth factors, members of the TNF pathway, and the extracellular matrix (ECM). Finally, the paradoxical effects of parathyroid hormone (PTH) on osteoblast apoptosis in vivo are considered in the perspective of a recent hypothesis speculating that this may be a key mechanism to explain the anabolic effects of the hormone.

Approximately 50% of neurofibromatosis type 1 (NF1) patients exhibit skeletal pathology, such as premature osteoporosis or pseudoarthroses. Loss of neurofibromin deregulates Ras signal transduction to affect generation of mitogen-activated protein kinase and Akt, both of which have been implicated in parathyroid hormone (PTH) anabolic mechanisms. Our aim was to determine if loss of neurofibromin impaired the anabolic effect of PTH on bone mass. Nf1 heterozygote (Nf1(+/-)) and wild type (Nf1(+/+)) mice were treated with recombinant human PTH(1-34) or vehicle once daily for 3-28 days. PTH enhanced mRNA expression of c-fos, junB, and fra2 in the distal femur metaphyses of both genotypes; expression of these transcripts was consistently lower in PTH-treated Nf1(+/-) mice. Despite lowered c-fos expression in Nf1(+/-) mice, PTH increased bone mass equivalently in both genotypes by 28 days. Ex vivo, Nf1 heterozygosity was associated with increased inducible osteoclasts in PTH-treated bone marrow cells and impairment of the actin stress fiber and cyclic adenosine monophosphate response to PTH in osteoprogenitors. Lower c-fos expression was previously thought to abrogate PTH responsiveness. Our results suggest crosstalk might occur between Ras signal transduction and the protein kinase A pathway in Nf1(+/-) mice. Ras signal transduction does not appear to be essential for the anabolic actions of PTH on bone. Because PTH was effective in the absence of Nf1, it may offer a useful approach to treat osteoporosis in NF1 patients.