Temporal role of macrophages in cancellous bone healing

Sandberg, Olof; Tätting, Love; Bernhardsson, Magnus; Aspenberg, Per

doi:10.1016/j.bone.2017.04.004

Cited by 32 publications

(37 citation statements)

References 15 publications

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“…Additionally, the following previous findings further corroborate our reasoning by demonstrating an irreplaceable role of M1 macrophages in bone repair. First, in animals where macrophages were depleted only at the proinflammatory stage, there was a severe impairment of fracture healing (9). Second, KO of M1 macrophage-derived cytokines (e.g., OSM, TNF-α, and IL-6) led to impaired fracture repair (11,32,33).…”

Section: Discussionmentioning

confidence: 99%

“…To determine a potential temporal role of macrophages in bone repair, a recent study showed that a single injection of a macrophage depleting agent (i.e., clodronate-containing liposomes) before bone injury decreased the density and strength of newly formed bones by half. However, injection of the clodronate at days 1 and 3 after a bone injury yielded a statistically insignificant effect (9). Since it might take 2-3 days for the clodronate-containing liposomes to deplete macrophages at fracture sites, we reasoned that the delayed injections might not efficiently deplete M1 macrophages.…”

Section: Introductionmentioning

confidence: 99%

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1,25-Dihydroxyvitamin D suppresses M1 macrophages and promotes M2 differentiation at bone injury sites

et al. 2018

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An indispensable role of macrophages in bone repair has been well recognized. Previous data have demonstrated the copresence of M1 macrophages and mesenchymal stem cells (MSCs) during the proinflammatory stage of bone repair. However, the exact role of M1 macrophages in MSC function and bone repair is unknown. This study aimed to define the role of M1 macrophages at bone injury sites via the function of 1,25-Dihydroxyvitamin D (1,25[OH]2D) in suppressing M1 but promoting M2 differentiation. We showed that 1,25(OH)2D suppressed M1 macrophage-mediated enhancement of MSC migration. Additionally, 1,25(OH)2D inhibited M1 macrophage secretion of osteogenic proteins (i.e., Oncostatin M, TNF-α, and IL-6). Importantly, the 1,25(OH)2D-mediated suppression of osteogenic function in M1 macrophages at the proinflammatory stage was associated with 1,25(OH)2D-mediated reduction of MSC abundance, compromised osteogenic potential of MSCs, and impairment of fracture repair. Furthermore, outside the proinflammatory stage, 1,25(OH)2D treatment did not suppress fracture repair. Accordingly, our data support 2 conclusions: (a) M1 macrophages are important for the recruitment and osteogenic priming of MSCs and, hence, are necessary for fracture repair, and (b) under vitamin D-sufficient conditions, 1,25(OH)2D treatment is unnecessary and can be detrimental if provided during the proinflammatory stage of fracture healing.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

1,25-Dihydroxyvitamin D suppresses M1 macrophages and promotes M2 differentiation at bone injury sites

et al. 2018

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“…The depletion of macrophages with clodronate liposomes impairs the healing of cancellous bone, both mechanically and morphometrically (Sandberg et al. 2017 ).…”

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confidence: 99%

Osteoblast precursors and inflammatory cells arrive simultaneously to sites of a trabecular-bone injury

Bernhardsson

Aspenberg

2018

Acta Orthopaedica

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Background and purpose — Fracture healing in the shaft is usually described as a sequence of events, starting with inflammation, which triggers mesenchymal tissue formation in successive steps. Most clinical fractures engage cancellous bone. We here describe fracture healing in cancellous bone, focusing on the timing of inflammatory and mesenchymal cell type appearance at the site of injuryMaterial and methods — Rats received a proximal tibial drill hole. A subgroup received clodronate-containing liposomes before or after surgery. The tibiae were analyzed with micro-CT and immunohistochemistry 1 to 7 days after injury.Results — Granulocytes (myeloperoxidase) appeared in moderate numbers within the hole at day 1 and then gradually disappeared. Macrophage expression (CD68) was seen on day 1, increased until day 3, and then decreased. Mesenchymal cells (vimentin) had already accumulated in the periphery of the hole on day 1. Mesenchymal cells dominated in the entire lesion on day 3, now producing extracellular matrix. A modest number of preosteoblasts (RUNX2) were seen on day 1 and peaked on day 4. Osteoid was seen on day 4 in the traumatized region, with a distinct border to the uninjured surrounding marrow. Clodronate liposomes given before the injury reduced the volume of bone formation at day 7, but no reduction in macrophage numbers could be detected.Interpretation — The typical sequence of events in shaft fractures was not seen. Mesenchymal cells appeared simultaneously with granulocyte and macrophage arrival. Clodronate liposomes, known to reduce macrophage numbers, seemed to be associated with the delineation of the volume of tissue to be replaced by bone. Most fracture healing studies in animal models concern cortical bone in shafts. However, most fractures in patients occur in cancellous bone in the metaphysis, such as the distal radius or in the vertebrae. A growing body of evidence suggests that there are important differences between the healing processes in cortical and cancellous bone.

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“…A growing number of studies demonstrate the immune systems involvement in fracture healing -including macrophages. [37][38][39][40][41] Macrophages are a subtype of inflammatory cells responsible for removing debris and pathogens by engulfing them through phagocytosis and have also been shown to be important for fracture healing.…”

Section: Inflammatory Cells Involvement In Bone Healing -Macrophagesmentioning

confidence: 99%

Healing Processes in Cancellous Bone

Bernhardsson

2018

Linköping University Medical Dissertations

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Många har varit inblandade och bidragit till att denna avhandling blev till och jag är oerhört tacksam inför alla som jag har fått träffa under färden! Det finns dock de som jag vill uttrycka några ytterligare ord om vördnad till: Per Aspenberg, utan dig hade jag inte varit där jag är idag, tack för att du trodde på mig. Din glöd må ha slocknat, men den lever vidare i oss alla som har berörts av dig. Anna Fahlgren, Jörg Schilcher och Pernilla Eliasson, för att ni hjälpte mig att ro denna avhandling i hamn. Ert enorma stöd och rådgivning har varit ovärderlig. Olof Sandberg, för att du visade vägen och hade tålamod med mig och alla mina frågor i början. Malin Hammerman, Parmis Blomgran, Love Tätting, Franciele Dietrich-Zagonel, Cornelia Bratengeier och Mehdi Amirhosseini, för all er hjälp, samarbete och sällskap på labbet samt kontoret. Alla som jobbat/jobbar på djuravdelningen, tack för ert alltid positiva bemötande och villighet att ställa upp när man frågar om hjälp. Alla på tidigare KEF och på Cellbiologen plan 10, tack för trevligt sällskap i fikarummet. Mina föräldrar och syskon med familjer, för den trygghet och uppmuntran ni ger mig som får mig att våga ta det extra steget. Min älskade fru Varre, hade jag inte haft dig vid min sida hade denna resa varit betydligt tuffare. Du håller mig uppe vid motgång och får mig att blicka framåt istället; med samma engagemang delar du också min glädje vid framgång.

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Temporal role of macrophages in cancellous bone healing

Cited by 32 publications

References 15 publications

1,25-Dihydroxyvitamin D suppresses M1 macrophages and promotes M2 differentiation at bone injury sites

1,25-Dihydroxyvitamin D suppresses M1 macrophages and promotes M2 differentiation at bone injury sites

Osteoblast precursors and inflammatory cells arrive simultaneously to sites of a trabecular-bone injury

Healing Processes in Cancellous Bone

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