Treatment with Carnitine Enhances Bone Fracture Healing under Osteoporotic and/or Inflammatory Conditions

Aydın, Ali; Halıcı, Zekai; Albayrak, Abdulmecit; Polat, Beyzagül; Karakuş, Emre; Yıldırım, Ömer Selim; Bayır, Yasin; Çadırcı, Elif; Ayan, Arif Kürşad; Aksakal, Ahmet Murat

doi:10.1111/bcpt.12384

Cited by 20 publications

(21 citation statements)

References 41 publications

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“…One of these cytokines is IL-6, which is known as a crucial factor for the recruitment of inflammatory cells [41, 72]. In addition, several studies demonstrated increased IL-6 expression after tissue injury in oestrogen-deficient mice [15, 16]. In the present study, we found higher IL-6 expression in the periosteal cells of OVX-mice.…”

Section: Discussionsupporting

confidence: 71%

“…Furthermore, the immune response is altered when the system is challenged. For example, the inflammatory response was increased in oestrogen-deficient mice after induction of paw inflammation or rheumatoid arthritis [15–17]. During wound healing, pro-inflammatory cytokines were up-regulated in rodents subjected to ovariectomy (OVX), resulting in delayed skin repair [18, 19].…”

Section: Introductionmentioning

confidence: 99%

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The inflammatory phase of fracture healing is influenced by oestrogen status in mice

Haffner‐Luntzer¹,

Fischer²,

Prystaz³

et al. 2017

Eur J Med Res

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BackgroundFracture healing is known to be delayed in postmenopausal, osteoporotic females under oestrogen-deficient conditions. Confirming this, experimental studies demonstrated impaired callus formation in ovariectomised animals. Oestrogen-deficiency is known to affect the immune system and the inflammatory response during wound healing. Because a balanced immune response is required for proper bone healing, we were interested to ascertain whether the early immune response after facture is affected by oestrogen depletion.MethodsTo address the above question, female mice received either a bilateral ovariectomy (OVX) or were sham-operated, and femur osteotomy was performed 8 weeks after OVX/sham operation. The effects of OVX on the presence of immune cells and pro-inflammatory cytokines were evaluated by flow cytometry and immunohistochemistry of the fracture calli on days 1 and 3 after fracture.ResultsOne day after fracture, immune cell numbers and populations in the fracture haematoma did not differ between OVX- and sham-mice. However, on day 3 after fracture, OVX-mice displayed significantly greater numbers of neutrophils. Local expression of the oestrogen-responsive and pro-inflammatory cytokine midkine (Mdk) and interleukin-6 (IL-6) expression in the fracture callus were increased in OVX-mice on day 3 after fracture compared with sham-mice, indicating that both factors might be involved in the increased presence of neutrophils. Confirming this, Mdk-antibody treatment decreased the number of neutrophils in the fracture callus and reduced local IL-6 expression in OVX-mice.ConclusionsThese data indicate that oestrogen-deficiency influences the early inflammatory phase after fracture. This may contribute to delayed fracture healing after oestrogen depletion.

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Section: Discussionsupporting

confidence: 71%

Section: Introductionmentioning

confidence: 99%

The inflammatory phase of fracture healing is influenced by oestrogen status in mice

Haffner‐Luntzer¹,

Fischer²,

Prystaz³

et al. 2017

Eur J Med Res

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“…S1 , A and B). As a previous study has established, interruption of estrogen is associated with the inflammatory process in bone, featured by increasing pro-inflammatory cytokines 22 . The expressions of TNF- α and IL 1-β in serum were compared between sham and OVX mice, and implied an inflammatory skeletal microenvironment in OVX mice (Fig.…”

Section: Resultsmentioning

confidence: 78%

Autophagy Maintains the Function of Bone Marrow Mesenchymal Stem Cells to Prevent Estrogen Deficiency-Induced Osteoporosis

Qi¹,

Zhang²,

Ma³

et al. 2017

Theranostics

151

120

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Rationale: The impaired function of endogenous bone marrow mesenchymal stem cells (BMMSCs) is a determinant in the development of osteoporosis (OP). Recent researches have proved that autophagy plays an important role in maintenance of skeletal phenotype. However, whether autophagy affects the development of OP through regulating the function of BMMSCs remains elusive.Methods: Ovariectomy (OVX)-induced OP model and sham model were established in 8-week-old C57 mice. The differentiation and immunoregulation properties of BMMSCs from two models were examined by osteogenic/adipogenic induction in vitro and treatment of a dextran sulfate sodium (DSS)-induced mice colitis model in vivo. We evaluated autophagy activity in sham and OVX BMMSCs by quantitative real time-polymerase chain reaction (qRT-PCR), western blotting, laser confocal microscopy and transmission electron microscopy (TEM). Finally, to testify the effects of rapamycin, short hairpin RNA (shRNA) -BECN1 (shBECN1) and shRNA-ATG5 (shATG5), we performed Alizarin Red staining and Oil Red O staining to detect lineage differentiations of BMMSCs, and carried out micro-CT, calcein staining and Oil Red O staining to assess the skeletal phenotype.Results: BMMSCs from OVX-induced OP model mice exhibited decreased osteogenic differentiation, increased adipogenic differentiation and impaired immunoregulatory capacity. Furthermore, autophagy decreased both in bone marrow and BMMSCs of osteoporotic mice. Importantly, regulation of autophagy directly affects the functions of BMMSCs, including differentiation and immunoregulatory capacities. Moreover, treatment with rapamycin rescued the function of endogenous BMMSCs and attenuated the osteoporotic phenotype in OVX mice.Conclusion: Our findings suggest that autophagy regulates the regenerative function of BMMSCs and controls the development of OP. The restoration of autophagy by rapamycin may provide an effective therapeutic method for osteoporosis.

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“…The skeletal and immune systems are closely linked, as shown in postmenopausal osteoporotic females and estrogen-deficient rodents [ 6 , 7 , 8 , 9 , 36 ]. In addition, the immune response to injury is altered under estrogen-deficiency [ 10 , 11 , 13 , 37 , 38 ]. Regarding fracture healing, OVX-mice displayed increased systemic serum Mdk levels on day 10 after fracture [ 39 ], increased local Mdk and IL-6 expression and more neutrophils on day 3 in the fracture callus, thus indicating a misbalanced immune response after fracture under estrogen-deficient conditions [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Influence of Menopause on Inflammatory Cytokines during Murine and Human Bone Fracture Healing

Fischer

Kalbitz

Müller‐Graf

et al. 2018

IJMS

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Postmenopausal females display a chronic inflammatory phenotype with higher levels of circulating pro-inflammatory cytokines. Furthermore, the inflammatory response to injury may be altered under estrogen-deficiency, because it was shown previously that estrogen-deficient mice displayed increased levels of the inflammatory cytokines Midkine (Mdk) and Interleukin-6 (IL-6) in the early fracture hematoma. Because a balanced immune response to fracture is required for successful bone regeneration, this might contribute to the delayed fracture healing frequently observed in osteoporotic, postmenopausal fracture patients. In this study, we aimed to investigate whether further cytokines in addition to Mdk and IL-6 might be affected by estrogen-deficiency after fracture in mice and whether these cytokines are also relevant during human fracture healing. Additionally, we aimed to investigate whether serum from male vs. female fracture patients affects osteogenic differentiation of human mesenchymal stem cells (MSCs). To address these questions, female mice were either sham-operated or ovariectomized (OVX) and subjected to standardized femur osteotomy. A broad panel of pro- and anti-inflammatory cytokines was determined systemically and locally in the fracture hematoma. In a translational approach, serum was collected from healthy controls and patients with an isolated fracture. Mdk and IL-6 serum levels were determined at day 0, day 14 and day 42 after fracture. Subgroup analysis was performed to investigate differences between male and female fracture patients after menopause. In an in vitro approach, human MSCs were cultured with the collected patient serum and osteogenic differentiation was assessed by qPCR and alkaline-phosphatase staining. Our results suggest an important role for the pro-inflammatory cytokines Mdk and IL-6 in the response to fracture in estrogen-deficient mice among all of the measured inflammatory mediators. Notably, both cytokines were also significantly increased in the serum of patients after fracture. However, only Mdk serum levels differed significantly between male and female fracture patients after menopause. MSCs cultivated with serum from female fracture patients displayed significantly reduced osteogenic differentiation, which was attenuated by Mdk-antibody treatment. In conclusion, our study demonstrated increased Mdk levels after fracture in OVX mice and female fracture patients after menopause. Because Mdk is a negative regulator of bone formation, this might contribute to impaired osteoporotic fracture healing.

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Treatment with Carnitine Enhances Bone Fracture Healing under Osteoporotic and/or Inflammatory Conditions

Cited by 20 publications

References 41 publications

The inflammatory phase of fracture healing is influenced by oestrogen status in mice

The inflammatory phase of fracture healing is influenced by oestrogen status in mice

Autophagy Maintains the Function of Bone Marrow Mesenchymal Stem Cells to Prevent Estrogen Deficiency-Induced Osteoporosis

Influence of Menopause on Inflammatory Cytokines during Murine and Human Bone Fracture Healing

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