Role of signaling pathways in age-related orthopedic diseases: focus on the fibroblast growth factor family.

Fibroblast growth factor (FGF) signaling encompasses a multitude of functions, including regulation of cell proliferation, differentiation, morphogenesis, and patterning. FGFs and their receptors (FGFR) are crucial for adult tissue repair processes. Aberrant FGF signal transduction is associated with various pathological conditions such as cartilage damage, bone loss, muscle reduction, and other core pathological changes observed in orthopedic degenerative diseases like osteoarthritis (OA), intervertebral disc degeneration (IVDD), osteoporosis (OP), and sarcopenia. In OA and IVDD pathologies specifically, FGF1, FGF2, FGF8, FGF9, FGF18, FGF21, and FGF23 regulate the synthesis, catabolism, and ossification of cartilage tissue. Additionally, the dysregulation of FGFR expression (FGFR1 and FGFR3) promotes the pathological process of cartilage degradation. In OP and sarcopenia, endocrine-derived FGFs (FGF19, FGF21, and FGF23) modulate bone mineral synthesis and decomposition as well as muscle tissues. FGF2 and other FGFs also exert regulatory roles. A growing body of research has focused on understanding the implications of FGF signaling in orthopedic degeneration. Moreover, an increasing number of potential targets within the FGF signaling have been identified, such as FGF9, FGF18, and FGF23. However, it should be noted that most of these discoveries are still in the experimental stage, and further studies are needed before clinical application can be considered. Presently, this review aims to document the association between the FGF signaling pathway and the development and progression of orthopedic diseases. Besides, current therapeutic strategies targeting the FGF signaling pathway to prevent and treat orthopedic degeneration will be evaluated.

Nociception-induced spatial and temporal plasticity of synaptic connection and function in the hippocampal formation of rats: a multi-electrode array recording.

BACKGROUND: Pain is known to be processed by a complex neural network (neuromatrix) in the brain. It is hypothesized that under pathological state, persistent or chronic pain can affect various higher brain functions through ascending pathways, leading to co-morbidities or mental disability of pain. However, so far the influences of pathological pain on the higher brain functions are less clear and this may hinder the advances in pain therapy. In the current study, we studied spatiotemporal plasticity of synaptic connection and function in the hippocampal formation (HF) in response to persistent nociception. RESULTS: On the hippocampal slices of rats which had suffered from persistent nociception for 2 h by receiving subcutaneous bee venom (BV) or formalin injection into one hand paw, multisite recordings were performed by an 8 x 8 multi-electrode array probe. The waveform of the field excitatory postsynaptic potential (fEPSP), induced by perforant path electrical stimulation and pharmacologically identified as being activity-dependent and mediated by ionotropic glutamate receptors, was consistently positive-going in the dentate gyrus (DG), while that in the CA1 was negative-going in shape in naïve and saline control groups. For the spatial characteristics of synaptic plasticity, BV- or formalin-induced persistent pain significantly increased the number of detectable fEPSP in both DG and CA1 area, implicating enlargement of the synaptic connection size by the injury or acute inflammation. Moreover, the input-output function of synaptic efficacy was shown to be distinctly enhanced by the injury with the stimulus-response curve being moved leftward compared to the control. For the temporal plasticity, long-term potentiation produced by theta burst stimulation (TBS) conditioning was also remarkably enhanced by pain. Moreover, it is strikingly noted that the shape of fEPSP waveform was drastically deformed or split by a TBS conditioning under the condition of persistent nociception, while that in naïve or saline control state was not affected. All these changes in synaptic connection and function, confirmed by the 2-dimentional current source density imaging, were found to be highly correlated with peripheral persistent nociception since pre-blockade of nociceptive impulses could eliminate all of them. Finally, the initial pharmacological investigation showed that AMPA/KA glutamate receptors might play more important roles in mediation of pain-associated spatiotemporal plasticity than NMDA receptors. CONCLUSION: Peripheral persistent nociception produces great impact upon the higher brain structures that lead to not only temporal plasticity, but also spatial plasticity of synaptic connection and function in the HF. The spatial plasticity of synaptic activities is more complex than the temporal plasticity, comprising of enlargement of synaptic connection size at network level, deformed fEPSP at local circuit level and, increased synaptic efficacy at cellular level. In addition, the multi-synaptic model established in the present investigation may open a new avenue for future studies of pain-related brain dysfunctions at the higher level of the neuromatrix.

[Influence of the depth of retained denatured dermis on the survival rate of grafted skin in burn swine with deep partial-thickness burn].

OBJECTIVE: To explore the influence of the thickness of retained denatured dermis on the survival rate of grafted skin in swine with deep partial-thickness burn. METHODS: Four deep partial-thickness wounds were reproduced respectively on both sides of spine in 7 Chinese domestic pigs. The wounds of 6 pigs were divided into 0.25, 0.50, 0.75, and 1.00 mm groups with 12 wounds in each group according to the random number table. Tangential excision and auto-skin grafting were performed. Before the tangential excision, 1 tissue specimen was harvested from the center of each remaining wound for the estimation of the depth of burn, and histological observation was done. After the tangential excision, 1 tissue specimen was harvested from the area near the center of each wound for the measurement of the depth of retained denatured dermis with histological examination. The 8 wounds of one pig were set as the control group, and the operation was done, and then they were treated with exposure treatment after biopsy specimens were taken with above-mentioned method. The general condition of wounds in 5 groups was observed from immediately after injury to post injury month (PIM) 3. On post injury day (PID) 7, the survival rate of grafted skin was observed in 0.25, 0.50, 0.75, and 1.00 mm groups. Wound healing time was recorded. At PIM 3, the specimens were harvested from the wounds of 5 groups, and their ultra microstructures were observed by transmission electron microscope. Data were processed with rank-sum test, one-way analysis of variance, and LSD test. RESULTS: The depth of the burn tissue was (1.120 ± 0.211) mm. The depths of retained denatured dermis in 0.25, 0.50, 0.75, and 1.00 mm groups were respectively (0.830 ± 0.031), (0.701 ± 0.010), (0.382 ± 0.031), and (0.141 ± 0.040) mm. At PID 8, all grafted skin in 0.25 and 0.50 mm groups became necrotic; most grafted skin in 0.75 mm group was necrotic; most grafted skin in 1.00 mm group survived with only a few became necrotic and separated from the wounds. The scabs were gradually separated from the wounds of control group. On PID 15, the grafted skin which did not survive in 0.25, 0.50, and 0.75 mm groups was gradually separated from the wounds with exudate forming scab on the surface in varying degrees, while the wounds in 1.00 mm group were all healed, and the incidence of scabs formation was highest in control group. At PIM 3, scar contraction was found in 0.25, 0.50, 0.75 mm groups and control group, while no obvious scar was observed in 1.00 mm group. There were statistically significant differences in the survival rate of grafted skin in 0.25, 0.50, 0.75, and 1.00 mm groups (χ(2) = 19.421, P < 0.001). The survival rate was the highest in 1.00 mm group [70% (60%, 80%)], while the survival rate was 20% (0, 30%) in 0.75 mm group, and it was in both 0.25 and 0.50 mm groups with non-survival of all the grafted skin. There were statistically significant differences in the wound healing time among 5 groups (F = 41.450, P < 0.001). The wound healing time in 0.25 and 0.50 mm groups were respectively (18.2 ± 1.5), and (18.7 ± 2.3) d, not statistically significant different from that of control group [(18.4 ± 1.7) d, P values both above 0.05]. The wound healing time in 0.75 mm group [(14.9 ± 2.6) d] was significantly different from those of 0.25, 0.50 mm groups and control group (P values all below 0.01). The wound healing time in 1.00 mm group [(9.5 ± 1.2) d] was significantly shorter compared with that of the other 4 groups (P values all below 0.01). Before tangential excision, the zone of infiltration of the inflammatory cells was observed in the deep dermis of wounds in 5 groups. After tangential excision and before auto-skin grafting, the depth from the fault surface to the zone of infiltration of the inflammatory cells varied in 0.25, 0.50, 0.75, and 1.00 mm groups while more inflammatory cells were observed in control group. At PIM 3, many fibroblasts were observed in the dermis of wounds in 1.00 mm group with abundant rough endoplasmic reticulum and basically intact organelles. CONCLUSIONS: Performing autologous skin grafting on deep partial-thickness burn, in which the depth of retained denatured dermis was 0.10 mm, may help regenerate dermal function and alleviate scar formation.

[Histologic analysis and long-term effect of acellular dermal matrix combined with autologous thin split-thickness skin graft].

OBJECTIVE: To evaluate the long-term therapeutic effect and histologic result of ADM combined with autologous thin split-thickness skin graft. METHODS: 23 patients were treated with acellular dermal matrix (ADM) combined with autologous thin split-thickness skin graft. The patients were followed up at 3, 6, 12, and 18 months after operation. The histological analysis was also performed. RESULTS: 3, 6, 12, 18 months after operation, the composite skin grafts became smooth with no hypertrophic scar and hyperpigmentation. It was soft and elastic. The joints could move randomly. The histologic study showed the composite skin graft had a similar appearance as the normal skin. CONCLUSION: As for the treatment of wound, the composite skin graft with ADM is smooth and soft with good elasticity after transplantation, but it has no perspiration.