Utjecaj koštanih morfogenetskih proteina 2 i 7 na volumen kosti u štakora s uklonjenom štitnom i doštitnim žlijezdama [Effects of bone morphogenetic protein 2 and 7 on bone volume in rats with removed thyroid and parathyroid glands]

Dumić-Čule, Ivo (2016) Utjecaj koštanih morfogenetskih proteina 2 i 7 na volumen kosti u štakora s uklonjenom štitnom i doštitnim žlijezdama [Effects of bone morphogenetic protein 2 and 7 on bone volume in rats with removed thyroid and parathyroid glands]. PhD thesis, Sveučilište u Zagrebu.

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Abstract

BMP2 and 7 are used locally in FDA approved indications including complicated long bone fractures, non-unions, and spinal fusions. It is unknown whether their systemic release following a local implantation might impact systemically the bone metabolism. Furthermore, it is unknown whether systemic BMP effects on bone are direct or mediated by calciotropic hormones. Removal of thyroid and parathyroid glands (TPTx) in rats resulted in the decreased level of calciotropic hormones and afterwards we initiated the treatment with BMP2 or 7. The administered doses have been calculated according to published bioavailability data from preclinical BMP2 and 7 studies. Additionally, BMP2 and 7 were tested in vitro to estimate their influence on osteoblast and osteoclast activity. TPTx resulted in bone loss which was restored by systemic administration of 10-70 μg/kg of BMP2 and all doses of BMP7. BMP2 showed a higher capacity for increasing trabecular number, while BMP7 augmented trabecular thickness. In vitro experiments revealed that BMP2 and 7, when uncoupled, increased the number and activity of both osteoblasts and osteoclasts. Collectively, locally administered BMP2 and 7 from bone devices might become partially available in circulation but will not mediate a systemic bone loss.

Abstract in Croatian

Koštani morfogenetski proteini (BMP)2 i 7 nakon niza kliničkih studija odobreni su od strane FDA za liječenje kompliciranih fraktura tibije te za spinalnu fuziju. Nakon lokalne ugradnje naprave s BMP2 ili 7 manja količina oslobađa se u sistemsku cirkulaciju. Do sada izravni učinak oslobođenih molekula BMP2 i 7 na koštani metabolizam nije istražen. Razvili smo štakorski model tireoparatireoidektomije (TPTx) sa smanjenom razinom kalciotropnih hormona na kojem smo testirali sistemski učinak BMP2 i 7. Primjenjene doze BMP2 i 7 određene su prema objavljenim rezultatima farmakodinamike i otpuštanja s mjesta lokalne primjene. TPTx operacija rezultirala je gubitkom koštanog volumena, koji je nadoknađen primjenom 10-70 μg/kg BMP2 i 10-250 μg/kg BMP7. BMP2 kvalitetnije je nadoknadio broj trabekula, dok je BMP7 prvenstveno djelovao da debljinu trabekula. In vitro eksperimenti pokazali su da BMP2 i 7 povećavaju aktivnost i broj osteoblasta i osteoklasta kad stanice nisu u međusobnoj interakciji. BMP2 i 7 povećavaju koštani volumen u životinja bez kalciotropnih hormona, što potvrđuje njihov izravan efekt. Zaključno, BMP2 i 7 koji se otpuste u sistemsku cirkulaciju nakon lokalne implantacije neće uzrokovati gubitak koštanog volumena.

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