Abstract
Bone tissue is densely innervated, and there is increasing evidence for a neural control of bone metabolism. Semaphorin-3A is a very important regulator of neuronal targeting in the peripheral nervous system as well as in angiogenesis, and knockout of the Semaphorin-3A gene induces abnormal bone and cartilage development. We analyzed the spatial and temporal expression patterns of Semaphorin-3A signaling molecules during endochondral ossification, in parallel with the establishment of innervation. We show that osteoblasts and chondrocytes differentiated in vitro express most members of the Semaphorin-3A signaling system (Semaphorin-3A, Neuropilin-1, and Plexins-A1 and -A2). In vitro, osteoclasts express most receptor chains but not the ligand. In situ, these molecules are all expressed in the periosteum and by resting, prehypertrophic and hypertrophic chondrocytes in ossification centers before the onset of neurovascular invasion. They are detected later in osteoblasts and also osteoclasts, with differences in intensity and regional distribution. Semaphorin-3A and Neuropilin-1 are also expressed in the bone marrow. Plexin-A3 is not expressed by bone cell lineages in vitro. It is detected early in the periosteum and hypertrophic chondrocytes. After the onset of ossification, this chain is restricted to a network of cell processes in close vicinity to the cells lining the trabeculae, similar to the pattern observed for neural markers at the same stages. After birth, while the density of innervation decreases, Plexin-A3 is strongly expressed by blood vessels on the ossification front. In conclusion, Semaphorin-3A signaling is present in bone and seems to precede or coincide at the temporal but also spatial level with the invasion of bone by blood vessels and nerve fibers. Expression patterns suggest Plexin-A3/Neuropilin-1 as a candidate receptor in target cells for the regulation of bone innervation by Semaphorin-3A.
Highlights
Work as well as recent immunocytochemical studies have highlighted the rich innervation of bone (Calvo and Forteza-Vila, 1969; Serre et al, 1999)
It has been shown that Semaphorin-3A (Sema-3A) signaling is very important for neuronal targeting in the peripheral nervous system (PNS), as shown for trigeminal and dorsal root ganglia which are involved in bone innervation (Kitsukawa et al, 1997; Taniguchi et al, 1997; Ulupinar et al, 1999)
We show that all components of the Sema-3A signaling system are expressed in mature stages of all 3 bone cell lineages, with the exception of Plx-A3
Summary
Work as well as recent immunocytochemical studies have highlighted the rich innervation of bone (Calvo and Forteza-Vila, 1969; Serre et al, 1999). The presence in bone of cell processes labeled with neural tip markers like synaptophysin has been documented Overall, these data provide evidence for the existence of functional nerve fibres within the bone tissue (Gronblad et al, 1984; Hohmann et al, 1986; Bjurholm et al, 1988; Serre et al, 1999). As early as embryonic day (E), nerve fibres appear in the perichondrium of the diaphysis of rat long bones They become functional at E18-19, when neural tips are formed and neuropeptide expression starts (Sisask et al, 1995; Sisask et al, 1996). The aim of our study was to investigate the expression of the molecules in the Sema-3A signaling network during skeletal development, focusing on the spatial and temporal relationship with nerve fibre growth
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