Five to ten percent of fractures fail to heal normally leading to additional surgery, morbidity, and altered quality of life. Fracture healing involves the coordinated action of stem cells primarily coming from the periosteum which differentiate into the chondrocytes and osteoblasts, forming first the soft (cartilage) callus followed by the hard (bone) callus. These stem cells are accompanied by a vascular invasion that appears critical for the differentiation process and which may enable the entry of osteoclasts necessary for the remodeling of the callus into mature bone. However, more research is needed to clarify the signaling events that activate the osteochondroprogenitor cells of periosteum and stimulate their differentiation into chondrocytes and osteoblasts. Ultimately a thorough understanding of the mechanisms for differential regulation of these osteochondroprogenitors will aid in the treatment of bone healing and the prevention of delayed union and nonunion of fractures. In this review, evidence supporting the concept that the periosteal cells are the major cell sources of skeletal progenitors for the fracture callus will be discussed. The osteogenic differentiation of periosteal cells manipulated by Wnt/b-catenin, TGF/BMP, Ihh/PTHrP, and IGF-1/PI3K–Akt signaling in fracture repair will be examined. The effect of physical (hypoxia and hyperoxia) and chemical factors (reactive oxygen species) as well as the potential coordinated regulatory mechanisms in the periosteal progenitor cells promoting osteogenic differentiation will also be discussed. Understanding the regulation of periosteal osteochondroprogenitors during fracture healing could provide insight into possible therapeutic targets and thereby help to enhance future fracture healing and bone tissue engineering approaches.
Periosteum plays an indispensable role in bone repair and reconstruction. To recapitulate the remarkable regenerative capacity of periosteum, a biomimetic tissue-engineered periosteum (TEP) was constructed via layer-by-layer bottom-up strategy utilizing polycaprolactone (PCL), collagen, and nano-hydroxyapatite composite nanofiber sheets seeded with bone marrow stromal cells (BMSCs). When combined with a structural bone allograft to repair a 4 mm segmental bone defect created in the mouse femur, TEP restored donor-site periosteal bone formation, reversing the poor biomechanics of bone allograft healing at 6 weeks post-implantation. Further histologic analyses showed that TEP recapitulated the entire periosteal bone repair process, as evidenced by donor-dependent formation of bone and cartilage, induction of distinct CD31 type H endothelium, reconstitution of bone marrow and remodeling of bone allografts. Compared to nanofiber sheets without BMSC seeding, TEP eliminated the fibrotic tissue capsule elicited by nanofiber sheets, leading to a marked improvement of osseointegration at the compromised periosteal site. Taken together, our study demonstrated a novel layer-by-layer engineering platform for construction of a versatile biomimetic periosteum, enabling further assembly of a multi-component and multifunctional periosteum replacement for bone defect repair and reconstruction.
Zoledronic acid seemed the most effective in preventing vertebral fracture, nonvertebral fracture, and any fracture, and alendronate or zoledronic acid seemed the most effective in preventing hip fracture. Uncertainty still remains and future studies are needed to accurately evaluate the comparative efficacy of bisphosphonates.
The present meta-analysis of real-world data does not suggest that IBT is associated with AP. Although we should continue to remain vigilant, IBTs should be regarded as reasonable options to consider adding to the regimen of a patient with type 2 diabetes.
Ovariectomy (OVX) can cause bone loss in rats, but little is known about how it also induces lumbar intervertebral disc degeneration (LVD). This study investigated how estrogen deficiency affected intervertebral discs in OVX rats. Thirty 3-month-old female Sprague-Dawley rats were divided randomly into three equal groups. The baseline control group (BL) was killed at the beginning of the experiment. An ovariectomy was performed in 10 rats (OVX group) and another group of 10 rats was subjected to a sham surgery (Sham group). The OVX rats were untreated after the surgery to allow for the development of moderate osteopenia. Bone mineral density (BMD) measurement and bone histomorphometric analysis were applied to the segments of lumbar spines in all rats killed 6 months after surgery. The pathological changes of intervertebral discs were observed and the degree of LVD was scored by a histological scoring system. The BMD of the spines (L3-L5) in the OVX group decreased significantly compared with the Sham group. The bone volume indices in the OVX group were significantly lower, but the bone turnover rate parameters were significantly higher than those in the Sham group (P < 0.01). The histological scores for LVD in the OVX group were significantly higher than those in the Sham group (P< 0.01). There was a significant negative correlation between the BMD and Grade II discs in the OVX rats (P = 0.042). In conclusion, LVD occurs in the OVX rats and the degeneration of cartilage end plates may be a pathogenic factor in disc degeneration.
Investigations of teriparatide (rPTH) as a potential treatment for critical defects have demonstrated the predicted anabolic effects on bone formation, and significant non-anabolic effects on healing via undefined mechanisms. Specifically, studies in murine models of structural allograft healing demonstrated that rPTH treatment increased angiogenesis (vessels <30μm), and decreased arteriogenesis (>30 μm) and mast cell numbers, which lead to decreased fibrosis and accelerated healing. To better understand these non-anabolic effects, we interrogated osteogenesis, vasculogenesis and mast cell accumulation in mice randomized to placebo (saline), rPTH (20μg/kg/2days), or the mast cell inhibitor sodium cromolyn (SC) (24μg/kg/2days), via longitudinal micro-CT and multiphoton laser scanning microscopy (MPLSM), in a critical calvaria defect model. Micro-CT demonstrated that SC significantly increased defect window closure and new bone volume versus placebo (p<0.05), although these effects were not as great as rPTH. Interestingly, both rPTH and SC has similar inhibitory effects on arteriogenesis versus placebo (p<0.05) without affecting total vascular volume. MPLSM time course studies in untreated mice revealed that large numbers of mast cells were detected 1 day post-op (43 +/− 17), peaked at 6 days (76 +/− 6), and were still present in the critical defect at the end of the experiment on day 30 (20 +/− 12). In contrast, angiogenesis was not observed until day 4, and functional vessels were first observed on 6 days, demonstrating that mast cell accumulation precedes vasculogenesis. To confirm a direct role of mast cells on osteogenesis and vasculogenesis, we demonstrated that specific diphtheria toxin-α deletion in Mcpt5-Cre-iDTR mice results in similar affects as SC treatment in WT mice. Collectively, these findings demonstrate that mast cells inhibit bone defect healing by stimulating arteriogenesis associated with fibrotic scaring, and that an efficacious non-anabolic effect of rPTH therapy on bone repair is suppression of arteriogenesis and fibrosis secondary to mast cell inhibition.
Follicular helper T (Tfh) cells and follicular regulatory T (Tfr) cells are critical for the development and maintenance of germinal centre (GC) and humoral immune responses. Accumulating evidence has demonstrated that the dysregulation of either Tfh cells or Tfr cells contributes to the pathogenesis of autoimmune diseases. We aim to investigate the roles of circulating Tfh cells and circulating Tfr cells in the pathogenesis of primary biliary cholangitis (PBC). A total of 34 patients with PBC and 27 health individuals were enrolled in this study. Flow cytometry revealed that circulating Tfh (CD4 CXCR5 CD127 CD25 ) cells were increased, but Tfr (CD4 CXCR5 CD127 CD25 ) cells and ratio of Tfr/Tfh were dramatically decreased in PBC patients compared with healthy controls. The Tfr/Tfh ratio was negatively correlated with level of serum IgM. Meanwhile, we also observed effector memory (CCR7 PD-1 ) Tfh cells and Tfr cells were dramatically increased, but central memory (CCR7 PD-1 ) Tfh cells and Tfr cells were decreased in PBC patients compared with healthy controls. Effector memory Tfr cells were positively correlated with level of serum ALP. These results indicate that an imbalance of circulating Tfr cells and Tfh cells may be involved in the immunopathogenesis of PBC and may provide novel insight for the development of PBC therapies.
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