Characterization of the bone phenotype and fracture repair in osteopetrotic <i>Incisors absent</i> rats

McDonald, Michelle M.; Morse, Alyson; Peacock, Lauren; Mikulec, Kathy; Schindeler, Aaron; Little, David

doi:10.1002/jor.21293

Cited by 16 publications

(12 citation statements)

References 16 publications

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“…For ADO, the defective osteoclasts seem to regulate bone formation (75,81,96). This updated definition is also in alignment with the original description of the naturally occurring murine forms of osteopetrosis, depicting osteoclast-poor (ex the tl-rat, (151, 158, 159)) and -rich forms (ex the ia-rat, (211,212)). …”

Section: Updated Definition Of Clinical Osteopetrosissupporting

confidence: 53%

Genetics in Endocrinology: Autosomal dominant osteopetrosis revisited: lessons from recent studies

Bollerslev

Henriksen

Nielsen

et al. 2013

European Journal of Endocrinology

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Systematic studies of autosomal dominant osteopetrosis (ADO) were followed by the identification of underlying mutations giving unique possibilities to perform translational studies. What was previously designated ADO1 turned out to be a high bone mass phenotype caused by a missense mutation in the first propeller of LRP5, a region of importance for binding inhibitory proteins. Thereby, ADO1 cannot be regarded as a classical form of osteopetrosis but must now be considered a disease of LRP5 activation. ADO (Albers-Schönberg disease, or previously ADO2) is characterized by increased number of osteoclasts and a defect in the chloride transport system (ClC-7) of importance for acidification of the resorption lacuna (a form of Chloride Channel 7 Deficiency Osteopetrosis). Ex vivo studies of osteoclasts from ADO have shown that cells do form normally but have reduced resorption capacity and an expanded life span. Bone formation seems normal despite decreased osteoclast function. Uncoupling of formation from resorption makes ADO of interest for new strategies for treatment of osteoporosis. Recent studies have integrated bone metabolism in whole-body energy homeostasis. Patients with ADO may have decreased insulin levels indicating importance beyond bone metabolism. There seems to be a paradigm shift in the treatment of osteoporosis. Targeting ClC-7 might introduce a new principle of dual action. Drugs affecting ClC-7 could be antiresorptive, still allowing ongoing bone formation. Inversely, drugs affecting the inhibitory site of LRP5 might stimulate bone formation and inhibit resorption. Thereby, these studies have highlighted several intriguing treatment possibilities, employing novel modes of action, which could provide benefits to the treatment of osteoporosis.

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Section: Updated Definition Of Clinical Osteopetrosissupporting

confidence: 53%

Genetics in Endocrinology: Autosomal dominant osteopetrosis revisited: lessons from recent studies

Bollerslev

Henriksen

Nielsen

et al. 2013

European Journal of Endocrinology

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“…Current research has challenged this theory, showing no negative effects of potent antiresorptive agents on soft cartilage callus remodeling to achieve union . In addition, a lack of resorbing osteoclasts in ia/ia rats, and impaired osteoclast formation in mice treated with RANK:Fc both failed to alter normal cartilage callus remodeling …”

Section: Discussionmentioning

confidence: 99%

“…(3)(4)(5)(6)(7)(8)(9)(10) In addition, a lack of resorbing osteoclasts in ia/ia rats, and impaired osteoclast formation in mice treated with RANK:Fc both failed to alter normal cartilage callus remodeling. (13,14) In the current study we tested agents with three distinct mechanisms of action. First, two BPs, ZA and CLOD, which ablated osteoclast activity with uncertain effects on their MMP production; second, recombinant OPG, which abolished osteoclast formation and hence all residual MMPs that osteoclasts produce; and last, MMI270, which blocked MMPs from all potential cell sources.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the preponderance of experimental evidence contrasts with the widely accepted assumption that osteoclasts are vital to the removal of unmineralized cartilaginous soft callus concomitant with the ensuing hard callus formation, in a process known as endochondral ossification. (12) Endochondral union was not impaired in the osteopetrotic ia/ia rat in which osteoclasts are nonfunctional, (13) nor was it impaired in mice treated with RANK; Fc (murine RANK fused to the fragment crystallizable, Fc region region of human IgG1). (14) Hence, although osteoclast resorption is key to hard calls remodeling, it is evident the osteoclasts role in soft callus removal may not be imperative.…”

Section: Introductionmentioning

confidence: 99%

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Matrix Metalloproteinase–Driven Endochondral Fracture Union Proceeds Independently of Osteoclast Activity

McDonald

Morse

Mikulec

et al. 2013

Journal of Bone and Mineral Research

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As new insights into the complexities of endochondral fracture repair emerge, the temporal role of osteoclast activity remains ambiguous. With numerous antiresorptive agents available to treat bone disease, understanding their impact on bone repair is vital. Further, in light of recent work suggesting osteoclast activity may not be necessary during early endochondral fracture union, we hypothesize instead a pivotal role of matrix metalloproteinase (MMP) secreting cells in driving this process. Although the role of MMPs in fracture healing has been examined, no directly comparative experiments exist. We examined a number of antiresorptive treatments to either block osteoclast activity, including the potent bisphosphonates zoledronic acid (ZA) and clodronate (CLOD), which work via differing mechanisms, or antagonize osteoclastogenesis with recombinant OPG (HuOPG-Fc), comparing these directly to an inhibitor of MMP activity (MMI270). Endochondral ossification to union occurred normally in all antiresorptive groups. In contrast, MMP inhibition greatly impaired endochondral union, significantly delaying cartilage callus removal. MMP inhibition also produced smaller, denser hard calluses. Hard callus remodeling was, as expected, delayed with ZA, CLOD, and OPG treatment at 4 and 6 weeks, resulting in larger, more mineralized calluses at 6 weeks. As a result of reduced hard callus turnover, bone formation was reduced with antiresorptive agents at these time points. These results confirm that the achievement of endochondral fracture union occurs independently of osteoclast activity. Alternatively, MMP secretion by invading cells is obligatory to endochondral union. This study provides new insight into cellular contributions to bone repair and may abate concerns regarding antiresorptive therapies impeding initial fracture union.

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“…Closed femoral fractures were induced using an Einhorn apparatus (3-point bending device with a weight drop of 300 g) as described previously. (11) In brief, anesthesia was induced with an intraperitoneal injection of 75 mg/kg ketamine and 10 mg/kg xylazine. After surgery, animals were recovered on a heated pad and placed in recovery cages.…”

Section: Closed Femoral Fracturementioning

confidence: 99%

PTH(1-34) Treatment Increases Bisphosphonate Turnover in Fracture Repair in Rats

Murphy

Schindeler

Cantrill

et al. 2014

Journal of Bone and Mineral Research

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Bisphosphonates (BP) are antiresorptive drugs with a high affinity for bone. Despite the therapeutic success in treating osteoporosis and metabolic bone diseases, chronic BP usage has been associated with reduced repair of microdamage and atypical femoral fracture (AFF). The latter has a poor prognosis, and although anabolic interventions such as teriparatide ) have been suggested as treatment options, there is a limited evidence base in support of their efficacy. Because PTH acts to increase bone turnover, we hypothesized that it may be able to increase BP in turnover in the skeleton, which, in turn, may improve bone healing. To test this, we employed a mixture of fluorescent Alexa647-labelled pamidronate (Pam) and radiolabeled 14 C-ZA (zoledronic acid). These traceable BPs were dosed to Wistar rats in models of normal growth and closed fracture repair. Rats were cotreated with saline or 25 mg/kg/d PTH , and the effects on BP liberation and bone healing were examined by X-ray, micro-CT, autoradiography, and fluorescent confocal microscopy. Consistent with increased BP remobilization with PTH , there was a significant decrease in fluorescence in both the long bones and in the fracture callus in treated animals compared with controls. This was further confirmed by autoradiography for 14 C-ZA. In this model of acute BP treatment, callus bone volume (BV) was significantly increased in fractured limbs, and although we noted significant decreases in callus-bound BP with PTH (1-34) , these were not sufficient to alter this BV. However, increased intracellular BP was noted in resorbing osteoclasts, confirming that, in principle, PTH increases bone turnover as well as BP turnover.

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Characterization of the bone phenotype and fracture repair in osteopetrotic Incisors absent rats

Cited by 16 publications

References 16 publications

Genetics in Endocrinology: Autosomal dominant osteopetrosis revisited: lessons from recent studies

Genetics in Endocrinology: Autosomal dominant osteopetrosis revisited: lessons from recent studies

Matrix Metalloproteinase–Driven Endochondral Fracture Union Proceeds Independently of Osteoclast Activity

PTH(1-34) Treatment Increases Bisphosphonate Turnover in Fracture Repair in Rats

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