Manual therapy as an effective treatment for fibrosis in a rat model of upper extremity overuse injury

Authors

Geoffrey M. Bove, Michele Y. Harris, Huaqing Zhao, Mary F. Barbe

Abstract

Key clinical features of carpal tunnel syndrome and other types of cumulative trauma disorders of the hand and wrist include pain and functional disabilities. Mechanistic details remain under investigation but may involve tissue inflammation and/or fibrosis. We examined the effectiveness of modeled manual therapy (MMT) as a treatment for sensorimotor behavior declines and increased fibrogenic processes occurring in forearm tissues of rats performing a high repetition high force (HRHF) reaching and grasping task for 12 weeks. Young adult, female rats were examined: food restricted control rats (FRC, n = 12); rats that were trained for 6 weeks before performing the HRHF task for 12 weeks with no treatment (HRHF-CON, n = 11); and HRHF task rats received modeled manual therapy (HRHF-MMT, n = 5) for 5 days/week for the duration of the 12-week of task. Rats receiving the MMT expressed fewer discomfort-related behaviors, and performed progressively better in the HRHF task. Grip strength, while decreased after training, improved following MMT. Fibrotic nerve and connective tissue changes (increased collagen and TGF-β1 deposition) present in 12-week HRHF-CON rats were significantly decreased in 12-week HRHF-MMT rats. These observations support the investigation of manual therapy as a preventative for repetitive motion disorders.

Link to Article

http://dx.doi.org/10.1016/j.jns.2015.12.029

Arctic Ground Squirrels Limit Bone Loss during the Prolonged Physical Inactivity Associated with Hibernation

Authors

Samantha J. Wojda, Richard A. Gridley, Meghan E. McGee-Lawrence, Thomas D. Drummer, Ann Hess, Franziska Kohl, Brian M. Barnes, and Seth W. Donahue

Abstract

Prolonged disuse (e.g., physical inactivity) typically results in increased bone porosity, decreased mineral density, and decreased bone strength, leading to increased fracture risk in many mammals. However, bears, marmots, and two species of ground squirrels have been shown to preserve macrostructural bone properties and bone strength during long seasons of hibernation while they remain mostly inactive. Some small hibernators (e.g., 13-lined ground squirrels) show microstructural bone loss (i.e., osteocytic osteolysis) during hibernation, which is not seen in larger hibernators (e.g., bears and marmots). Arctic ground squirrels (Urocitellus parryii) are intermediate in size between 13-lined ground squirrels and marmots and are perhaps the most extreme rodent hibernator, hibernating for up to 8 mo annually with body temperatures below freezing. The goal of this study was to quantify the effects of hibernation and inactivity on cortical and trabecular bone properties in arctic ground squirrels. Cortical bone geometrical properties (i.e., thickness, cross-sectional area, and moment of inertia) at the midshaft of the femur were not different in animals sampled over the hibernation and active seasons. Femoral ultimate stress tended to be lower in hibernators than in summer animals, but toughness was not affected by hibernation. The area of osteocyte lacunae was not different between active and hibernating animals. There was an increase in osteocytic lacunar porosity in the hibernation group due to increased lacunar density. Trabecular bone volume fraction in the proximal tibia was unexpectedly greater in the hibernation group than in the active group. This study shows that, similar to other hibernators, arctic ground squirrels are able to preserve many bone properties during hibernation despite being physically inactive for up to 8 mo.

Link to Article

http://dx.doi.org/10.1086/684619

Dual function of Bmpr1a signaling in restricting preosteoblast proliferation and stimulating osteoblast activity in the mouse

Authors

Joohyun Lim, Yu Shi, Courtney M. Karner, Seung-Yon Lee, Wen-Chih Lee, Guangxu He, Fanxin Long

Abstract

Exogenous bone morphogenetic proteins (Bmp) are well known to induce ectopic bone formation, but the physiological effect of Bmp signaling on normal bone is not completely understood. By deleting the receptor Bmpr1a in osteoblast-lineage cells with Dmp1-Cre, we observed a dramatic increase in trabecular bone mass in postnatal mice, due to a marked increase in osteoblast number likely driven by hyperproliferation of Sp7+ preosteoblasts. Similarly, inducible deletion of Bmpr1a in Sp7-positive cells specifically in postnatal mice increased trabecular bone mass. However, deletion of Smad4 by the same approaches had only a minor effect, indicating that Bmpr1a signaling suppresses trabecular bone formation through effectors beyond Smad4. Besides increasing osteoblast number in the trabecular bone, deletion of Bmpr1a by Dmp1-Cre also notably reduced osteoblast activity, resulting in attenuation of periosteal growth. The impairment in osteoblast activity correlated with reduced mTORC1 signaling in vivo, whereas inhibition of mTORC1 activity abolished the induction of protein anabolism genes by Bmp2 in vitro. Thus, physiological Bmpr1a signaling in bone exerts dual function in both restricting preosteoblast proliferation and promoting osteoblast activity.

Link to Article

http://dx.doi.org/10.1242/dev.126227

A novel nano-copper-bearing stainless steel with reduced Cu2+ release only inducing transient foreign body reaction via affecting the activity of NF-κB and Caspase 3

Authors

Lei Wang, Ling Ren, Tingting Tang, Kerong Dai, Ke Yang, Yongqiang Hao

Abstract

Abstract: Foreign body reaction induced by biomaterials is a serious problem in clinical applications. Although 317L-Cu stainless steel (317L-Cu SS) is a new type of implant material with antibacterial ability and osteogenic property, the foreign body reaction level still needs to be assessed due to its Cu2+ releasing property. For this purpose, two macrophage cell lines were selected to detect cellular proliferation, apoptosis, mobility, and the secretions of inflammatory cytokines with the influence of 317L-Cu SS. Our results indicated that 317L-Cu SS had no obvious effect on the proliferation and apoptosis of macrophages; however, it significantly increased cellular migration and TNF-α secretion. Then, C57 mice were used to assess foreign body reaction induced by 317L-Cu SS. We observed significantly enhanced recruitment of inflammatory cells (primarily macrophages) with increased TNF-α secretion and apoptosis level in tissues around the materials in the early stage of implantation. With tissue healing, both inflammation and apoptosis significantly decreased. Further, we discovered that NF-κB pathway and Caspase 3 played important roles in 317L-Cu SS induced inflammation and apoptosis. We concluded that 317L-Cu SS could briefly promote the inflammation and apoptosis of surrounding tissues by regulating the activity of NF-κB pathway and Caspase 3. All these discoveries demonstrated that 317L-Cu SS has a great potential for clinical application.

Link to Article

http://dx.doi.org/10.2147/IJN.S90249

Osteoblast-specific Overexpression of Human WNT16 Increases both Cortical and Trabecular Bone Mass and Structure in Mice

Authors

Imranul Alama, Mohammed Alkhoulia, Rita L. Gerard-O’Rileya, Weston B. Wrighta, Dena Actona, Amie K. Graya, Bhavmik Patela, Austin M. Reillya, Kyung-Eun Limc, Alexander G. Roblingc, and Michael J. Econs

Abstract

Previous genome-wide association studies have identified common variants in genes associated with bone mineral density (BMD) and risk of fracture. Recently, we identified SNPs in WNT16 that were associated with peak BMD in premenopausal women. To further identify the role of Wnt16 in bone mass regulation, we created transgenic (TG) mice over-expressing human WNT16 in osteoblasts. We compared bone phenotypes, serum biochemistry, gene expression and dynamic bone histomorphometry between TG and wild-type (WT) mice. Compared to WT mice, WNT16-TG mice exhibited significantly higher whole body aBMD and BMC at 6 and 12 weeks of age in both male and female. Micro-CT analysis of trabecular bone at distal femur revealed 3-fold (male) and 14-fold (female) higher BV/TV, and significantly higher Tb.N, Tb.Th but lower Tb.Sp in TG mice compared to WT littermates in both sexes. Serum biochemistry analysis showed that male TG mice had higher serum ALP, OC, OPG, OPG/RANKL ratio as compared to WT mice. Also, lower CTX/TRAPc5b ratio was observed in TG mice compared to WT littermates in both male and female. Histomorphometry data demonstrated that both male and female TG mice had significantly higher cortical and trabecular MS/BS and BFR compared to sex-matched wild-type mice. Gene expression analysis demonstrated higher expression of Alp, OC, Opg, Opg/Rankl ratio in bone tissue in the transgenic mice compared to wild-type littermates. Our data indicate that WNT16 is critical for positive regulation of both cortical and trabecular bone mass and structure, and that this molecule might be targeted for therapeutic interventions to treat osteoporosis.

Link to Article

http://dx.doi.org/10.1210/en.2015-1281

Systemic Administration of Sclerostin Antibody Enhances Bone Morphogenetic Protein-Induced Femoral Defect Repair in a Rat Model

Authors

Brian A. Tinsley, MD; Alex Dukas, MD; Michael J. Pensak, MD; Douglas J. Adams, PhD; Amy H. Tang, BS; Michael S. Ominsky, PhD; Hua Zhu Ke, PhD; Jay R. Lieberman, MD

Abstract

Background: Recombinant human bone morphogenetic protein (rhBMP)-2 is a potent osteoinductive agent; however, its clinical use has been reduced because of safety and efficacy concerns. In preclinical studies involving a critical-sized defect in a rat model, sclerostin antibody (Scl-Ab) treatment increased bone formation within the defect but did not result in reliable healing. The purpose of the current study was to evaluate bone repair of a critical-sized femoral defect in a rat model with use of local implantation of rhBMP-2 combined with systemic administration of Scl-Ab.

Methods: A critical-sized femoral defect was created in rats randomized into three treatment groups: local rhBMP-2 and systemic Scl-Ab (Scl + BMP), local rhBMP-2 alone, and collagen sponge alone (operative control). The Scl + BMP group received local rhBMP-2 (10 μg) on a collagen sponge placed within the defect intraoperatively and then twice weekly injections of Scl-Ab (25 mg/kg) administered postoperatively. The femora were evaluated at twelve weeks with use of radiography, microcomputed tomography (microCT), histomorphometric analysis, and biomechanical testing.

Results: At twelve weeks, all Scl + BMP and rhBMP-2 only samples were healed. No femora healed in the operative control group. Histomorphometric analysis demonstrated more bone in the Scl + BMP samples than in the samples treated with rhBMP-2 alone (p = 0.029) and the control samples (p = 0.003). MicroCT revealed that the Scl + BMP group had a 90% greater bone volume within the defect region compared with the rhBMP-2 group and a 350% greater bone volume compared with the operative control group (p < 0.001). Biomechanical testing showed that the group treated with Scl + BMP had greater torsional strength and rigidity compared with the rhBMP-2 group (p < 0.001 and p = 0.047) and the intact femoral control group (p < 0.001). Torque to failure was lower in the rhBMP-2 group compared with the intact femoral control group (p < 0.002). Mean energy to failure was higher in the Scl + BMP samples compared with the rhBMP-2 only samples (p = 0.001).

Conclusions: In a critical-sized femoral defect in a rat model, local rhBMP-2 combined with systemic administration of Scl-Ab resulted in more robust healing that was stronger and more rigid than results for rhBMP-2 alone and intact nonoperative femora.

Clinical Relevance: Our study demonstrated that combining an osteoinductive agent with a systemically administered antibody that promotes bone formation can enhance bone repair and has potential as a therapeutic regimen in humans.

Link to Article

http://dx.doi.org/10.2106/JBJS.O.00171