Changes in the Mechanical Properties and Composition of Bone during Microdamage Repair

Authors

Gang Wang, Xinhua Qu, Zhifeng Yu

Abstract

Under normal conditions, loading activities result in microdamage in the living skeleton, which is repaired by bone remodeling. However, microdamage accumulation can affect the mechanical properties of bone and increase the risk of fracture. This study aimed to determine the effect of microdamage on the mechanical properties and composition of bone. Fourteen male goats aged 28 months were used in the present study. Cortical bone screws were placed in the tibiae to induce microdamage around the implant. The goats were euthanized, and 3 bone segments with the screws in each goat were removed at 0 days, 21 days, 4 months, and 8 months after implantation. The bone segments were used for observing microdamage and bone remodeling, as well as nanoindentation and bone composition, separately. Two regions were measured: the first region (R1), located 1.5 mm from the interface between the screw hole and bone; and the second region (R2), located>1.5 mm from the bone-screw interface. Both diffuse and linear microdamage decreased significantly with increasing time after surgery, with the diffuse microdamage disappearing after 8 months. Thus, screw implantation results in increased bone remodeling either in the proximal or distal cortical bone, which repairs the microdamage. Moreover, bone hardness and elastic modulus decreased with microdamage repair, especially in the proximal bone tissue. Bone composition changed greatly during the production and repair of microdamage, especially for the C (Carbon) and Ca (Calcium) in the R1 region. In conclusion, the presence of mechanical microdamage accelerates bone remodeling either in the proximal or distal cortical bone. The bone hardness and elastic modulus decreased with microdamage repair, with the micromechanical properties being restored on complete repair of the microdamage. Changes in bone composition may contribute to changes in bone mechanical properties.

Link To Article

http://dx.doi.org/10.1371/journal.pone.0108324

Novel EP4 Receptor Agonist-Bisphosphonate Conjugate Drug (C1) Promotes Bone Formation and Improves Vertebral Mechanical Properties in the Ovariectomized Rat Model of Postmenopausal Bone Loss

Authors

Careesa C. Liu, Sally Hu, Gang Chen PhD, John Georgiou PhD, Steve Arns PhD, Nag S. Kumar PhD, Robert N. Young PhD and Marc D. Grynpas PhD

Abstract

Current treatments for postmenopausal osteoporosis aim to either promote bone formation or inhibit bone resorption. The C1 conjugate drug represents a new treatment approach by chemically linking the anti-resorptive compound alendronate (ALN) with the anabolic agent prostanoid EP4 receptor agonist (EP4a) through a linker molecule (LK) to form a conjugate compound. This enables the bone-targeting ability of ALN to deliver EP4a to bone sites and mitigate the systemic side effects of EP4a, while also facilitating dual anti-resorptive and anabolic effects. In vivo hydrolysis is required to release the EP4a and ALN components for pharmacological activity. Our study investigated the in vivo efficacy of this drug in treating established bone loss using an ovariectomized (OVX) rat model of postmenopausal osteopenia. In a curative experiment, 3-month-old female Sprague-Dawley rats were OVX, allowed to lose bone for 7 weeks, then treated for 6 weeks. Treatment groups consisted of C1 conjugate at low and high doses, vehicle-treated OVX and sham, prostaglandin E2 (PGE2), and mixture of unconjugated ALN-LK and EP4a to assess the effect of conjugation. Results showed that weekly administration of C1 conjugate dose-dependently increased bone volume in trabecular bone, which partially or completely reversed OVX-induced bone loss in the lumbar vertebra and improved vertebral mechanical strength. The conjugate also dose-dependently stimulated endocortical woven bone formation and intracortical resorption in cortical bone, with high dose treatment increasing the mechanical strength but compromising the material properties. Conjugation between the EP4a and ALN-LK components was crucial to the drug's anabolic efficacy. To our knowledge, the C1 conjugate represents the first time that a combined therapy using an anabolic agent and the anti-resorptive compound ALN has shown significant anabolic effects which reversed established osteopenia.

Link To Article

http://dx.doi.org/10.1002/jbmr.2382

Connexin 43 Channels are Essential for Normal Bone Structure and Osteocyte Viability

Authors

Huiyun Xu PhD, Sumin Gu MD, Manuel A. Riquelme PhD, Sirisha Burra PhD, Danielle Callaway BS, Hongyun Cheng BS, Teja Guda PhD, James Schmitz BS, Roberto J. Fajardo PhD, Sherry L. Werner MD, Hong Zhao MS, Peng Shang PhD, Mark L. Johnson PhD, Lynda F. Bonewald PhD and Jean X. Jiang PhD

Abstract

Connexin (Cx) 43 serves important roles in bone function and development. Targeted deletion of Cx43 in osteoblasts or osteocytes leads to increased osteocyte apoptosis, osteoclast recruitment, and reduced biomechanical properties. Cx43 forms both gap junction channels and hemichannels, which mediate the communication between adjacent cells or between cell and extracellular environments, respectively. Two transgenic mouse models driven by a DMP1 promoter with the overexpression of dominant negative Cx43 mutants were generated to dissect the functional contribution of Cx43 gap junction channels and hemichannels in osteocytes. The R76W mutant blocks gap junction channel, but not hemichannel function, and the Δ130-136 mutant inhibits activity of both types of channels. Δ130-136 mice showed a significant increase in bone mineral density compared to WT and R76W mice. MicroCT analyses revealed a significant increase in total tissue and bone area in midshaft cortical bone of Δ130-136 mice. The bone marrow cavity was expanded, whereas the cortical thickness was increased and associated with increased bone formation along the periosteal area. However, there is no significant alteration in the structure of trabecular bone. Histologic sections of the midshaft showed increased apoptotic osteocytes in Δ130-136, but not in WT and R76W, mice which correlated with altered biomechanical and estimated bone material properties. Osteoclasts were increased along the endocortical surface in both transgenic mice with a greater effect in Δ130-136 mice which likely contributed to the increased marrow cavity. Interestingly, the overall expression of serum bone formation and resorption markers were higher in R76W mice. These findings suggest that osteocytic Cx43 channels play distinctive roles in the bone; hemichannels play a dominant role in regulating osteocyte survival, endocortical bone resorption and periosteal apposition, and gap junction communication is involved in the process of bone remodeling.

Link To Article

http://dx.doi.org/10.1002/jbmr.2374

Overuse Activity in the Presence of Scapular Dyskinesis Leads to Shoulder Tendon Damage in a Rat Model

Authors

Katherine E. Reuther, Stephen J. Thomas, Jennica J. Tucker, Rameen P. Vafa, Joshua A. Gordon, Stephen S. Liu, Adam C. Caro, Sarah M. Yannascoli, Andrew F. Kuntz, Louis J. Soslowsky

Abstract

Shoulder tendon injuries are common clinical conditions and are a significant source of pain and dysfunction. These conditions are more common in individuals who perform repetitive overhead activities and in individuals who have abnormal scapular kinematics, termed scapular dyskinesis (SD). However, the long term consequences associated with overuse activity in the presence of SD are unknown. Therefore, the objective of this study was to determine the effect of overuse in combination with SD on joint mechanics and properties of the rotator cuff and biceps tendons. A rat model of scapular dyskinesis was used. Ninety adult male Sprague–Dawley rats (400–450 g) were randomized into three groups: nerve transection (SD), sham nerve transection + overuse (OV), or nerve transection + overuse (SD + OV). Rats were sacrificed at 2, 4, and 8 weeks after surgery. Shoulder function and passive joint mechanics were evaluated over time and tendon properties (mechanical, histological, organizational, and compositional) were measured. Results demonstrated that overuse activity and SD are each independently detrimental to tendon properties (e.g., diminished mechanical properties, disorganized collagen). However, tendon damage caused by the addition of overuse may be worse, with more parameters altered, than damage caused by the addition of SD. This study helps define the mechanical mechanisms leading to tendon damage and provides a framework for distinguishing treatment strategies for active patients and those with abnormal scapular mechanics.

Link To Article

http://dx.doi.org/10.1007/s10439-014-1137-y

Fracture healing using degradable magnesium fixation plates and screws

Authors

Amy Chaya, BS, Sayuri Yoshizawa, DDS, PhD, Kostas Verdelis, DDS, PhD, Sabrina Noorani, MS, B.J. Costello, MD, DMD, Charles Sfeir, DDS, PhD

Abstract

Purpose Internal bone fixation devices made with permanent metals are associated with numerous long-term complications and may require removal. We hypothesized that fixation devices made with degradable magnesium alloys could provide an ideal combination of strength and degradation, facilitating fracture fixation and healing, while eliminating the need for implant removal surgery.

Methods Fixation plates and screws were machined from 99.9% pure magnesium and compared to titanium devices in a rabbit ulna fracture model. Magnesium device degradation and effect on fracture healing and bone formation was assessed after four weeks. Fracture healing with magnesium device fixation was compared to that of titanium devices using qualitative histological analysis and quantitative histomorphometry.

Results Microcomputed tomography showed device degradation after four weeks in vivo. In addition, 2D microCT slices and histological staining showed that magnesium degradation did not inhibit fracture healing or bone formation. Histomorphology revealed no difference in bone bridging fractures fixed with magnesium and titanium devices. Interestingly, abundant new bone was formed around magnesium devices, suggesting a connection between magnesium degradation and bone formation.

Conclusion Our results demonstrate potential for magnesium fixation devices in a loaded fracture environment. Furthermore, these results suggest that magnesium fixation devices may enhance fracture healing by encouraging localized new bone formation.

Link To Article

http://dx.doi.org/10.1016/j.joms.2014.09.007

An insulin-sensitizing thiazolidinedione, which minimally activates PPARγ, does not cause bone loss

Authors

Tomohiro Fukunaga, Wei Zou, Nidhi Rohatgi, Jerry R. Colca and Steven L. Teitelbaum

Abstract

Rosiglitazone is an insulin-sensitizing thiazolidinedione (TZD) which activates the transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ). While rosiglitazone effectively treats type II diabetes mellitus (T2DM), it carries substantial complications including increased fracture risk. This predisposition to fracture is consistent with the fact that PPARγ preferentially promotes formation of adipocytes at the cost of osteoblasts. Rosiglitazone-activated PPARγ, however, also stimulates osteoclast formation. A new TZD analog with low affinity for binding and activation of PPARγ but whose insulin-sensitizing properties mirror those of rosiglitazone, has been recently developed. Because of its therapeutic implications, we investigated the effects of this new TZD analog (MSDC-0602) on skeletal homeostasis, in vitro and in vivo. Confirming it activates the nuclear receptor in osteoclasts, rosiglitazone enhances expression of the PPARγ target gene, CD36. MSDC-0602, in contrast, minimally activates PPARγ and does not alter CD36 expression in the bone resorptive cells. Consistent with this finding, rosiglitazone increases RANKL-induced osteoclast differentiation and number whereas MSDC-0602 fails to do. To determine if this new TZD analog is bone sparing, in vivo, we fed adult male C57BL/6 mice MSDC-0602 or rosiglitazone. 6-months of a rosiglitazone diet results in a 35% decrease in bone mass with increased number of osteoclasts whereas that of MSDC-0602 fed mice is indistinguishable from control. Thus PPARγ-sparing eliminates the skeletal side effects of TZDs while maintaining their insulin-sensitizing properties.

Link To Article

http://dx.doi.org/10.1002/jbmr.2364