Novel Lipid Signaling Mediators for Mesenchymal Stem Cell Mobilization during Bone Repair.

INTRODUCTION: Mesenchymal stem and progenitor cells (MSCs), which normally reside in the bone marrow, are critical to bone health and can be recruited to sites of traumatic bone injury, contributing to new bone formation. The ability to control the trafficking of MSCs provides therapeutic potential for improving traumatic bone healing and therapy for genetic bone diseases such as hypophosphatasia. METHODS: In this study, we explored the sphingosine-1-phosphate (S1P) signaling axis as a means to control the mobilization of MSCs into blood and possibly to recruit MSCs enhancing bone growth. RESULTS: Loss of S1P receptor 3 (S1PR3) leads to an increase in circulating CD45-/CD29+/CD90+/Sca1 putative mesenchymal progenitor cells, suggesting that blocking S1PR3 may stimulate MSCs to leave the bone marrow. Antagonism of S1PR3 with the small molecule VPC01091 stimulated acute migration of CD45-/CD29+/CD90+/Sca1+ MSCs into the blood as early as 1.5 hours after treatment. VPC01091 administration also increased ectopic bone formation induced by BMP-2 and significantly increased new bone formation in critically sized rat cranial defects, suggesting that mobilized MSCs may home to injuries to contribute to healing. We also explored the possibility of combining S1P manipulation of endogenous host cell occupancy with exogenous MSC transplantation for potential use in combination therapies. Importantly, reducing niche occupancy of host MSCs with VPC01091 does not impede engraftment of exogenous MSCs. CONCLUSIONS: Our studies suggest that MSC mobilization through S1PR3 antagonism is a promising strategy for endogenous tissue engineering and improving MSC delivery to treat bone diseases.

Dynamic Functional Assessment of Hand Motion Using an Animation Glove: The Effect of Stenosing Tenosynovitis.

BACKGROUND: The aim of the present study is to determine whether an animation glove can be utilized to provide a reliable and reproducible assessment of dynamic hand function and whether this assessment is altered in the setting of hand pathology. METHODS: Ten subjects without known hand pathology and 11 subjects with known stenosing tenosynovitis were assessed on tasks involving hand function at varied speeds, including forceful and gradual making of a fist and the quick and slow grip of a baseball using an animation glove to record range of motion and measures of velocity (CyberGlove II). RESULTS: In normal subjects, peak extension and flexion velocity of the index and middle finger was highest in the metacarpophalangeal and lowest in the distal interphalangeal; however, the converse was true in the ring finger. In those subjects with stenosing tenosynovitis, the animation glove was able to detect a triggering event during assessment. Furthermore, there was a significant decrease in the maximum velocity of the proximal interphalangeal joint observed with the slow fist task in both flexion and extension (55%, P < .01) in the affected hand when compared with the unaffected hand. CONCLUSIONS: The CyberGlove II can be utilized in the dynamic functional analysis of the hand and is able to detect a triggering event in subjects with known stenosing tenosynovitis. Those subjects demonstrate a significant decrease in maximum velocity in slow fist tasks, highlighting the need for comprehensive assessment to ascertain the full extent of functional limitations that can occur in the setting of hand pathology.

Osteonecrosis of the femoral head: An update in year 2012.

Osteonecrosis is a phenomenon involving disruption to the vascular supply to the femoral head, resulting in articular surface collapse and eventual osteoarthritis. Although alcoholism, steroid use, and hip trauma remain the most common causes, several other etiologies for osteonecrosis have been identified. Basic science research utilizing animal models and stem cell applications continue to further elucidate the pathophysiology of osteonecrosis and promise novel treatment options in the future. Clinical studies evaluating modern joint-sparing procedures have demonstrated significant improvements in outcomes, but hip arthroplasty is still the most common procedure performed in these affected younger adults. Further advances in joint-preserving procedures are required and will be widely studied in the coming decade.

Cartilage abnormalities associated with defects of chondrocytic primary cilia in Bardet-Biedl syndrome mutant mice.

Primary cilia are found on nearly every mammalian cell, including osteocytes, fibroblasts, and chondrocytes. However, the functions of primary cilia have not been extensively studied in these cells, particularly chondrocytes. Interestingly, defects in the primary cilium result in skeletal defects such as polydactyly in Bardet-Biedl syndrome (BBS), a ciliary disorder that also results in obesity, retinopathy, and cognitive impairments. Wild-type mice and mutant mice of the ciliary proteins Bbs1, Bbs2, and Bbs6 were evaluated with respect to histological and biochemical differences in chondrocytes from articular cartilage and xiphoid processes. Using immunofluorescence microscopy, chondrocytic cilia were visualized from the load-bearing joints and non-load-bearing xiphoid processes. Significant differences in ciliary morphology were not identified between mutant and wild-type mice. However, after expanding chondrocytes in cell culture and implanting them in solid agarose matrix, it was seen that the fraction of ciliated cells in cultures from mutant mice was significantly lower than in the wild-type cultures (p < 0.05). In addition, in Safranin-O-stained whole joint sections, Bbs mutant mice had significantly lower articular joint thickness (p < 0.05) and lower proteoglycan content saturation (p < 0.05) than wild-type mice. Moreover, there were statistically significant differences of cell distribution between Bbs mutant and wild-type mice (p < 0.05), indicating that mutant articular cartilage had changes consistent with early signs of osteoarthritis. These data indicate that Bbs genes and their functions in the chondrocytic primary cilium are important for normal articular cartilage maintenance.