Metformin can mitigate skeletal dysplasia caused by Pck2 deficiency

Zheng Li; Muxin Yue; Boon Chin Heng; Yunsong Liu; Ping Zhang; Yongsheng Zhou

doi:10.1038/s41368-022-00204-1

International Journal of Oral Science ›› 2022, Vol. 14 ›› Issue (1) :54 DOI: 10.1038/s41368-022-00204-1

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Metformin can mitigate skeletal dysplasia caused by Pck2 deficiency

Zheng Li ¹^,²
, Muxin Yue ¹^,²
, Boon Chin Heng ²^,³
, Yunsong Liu ¹^,²
, Ping Zhang ¹^,²^,^e
, Yongsheng Zhou ¹^,²^,^f

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Abstract

As an important enzyme for gluconeogenesis, mitochondrial phosphoenolpyruvate carboxykinase (PCK2) has further complex functions beyond regulation of glucose metabolism. Here, we report that conditional knockout of Pck2 in osteoblasts results in a pathological phenotype manifested as craniofacial malformation, long bone loss, and marrow adipocyte accumulation. Ablation of Pck2 alters the metabolic pathways of developing bone, particularly fatty acid metabolism. However, metformin treatment can mitigate skeletal dysplasia of embryonic and postnatal heterozygous knockout mice, at least partly via the AMPK signaling pathway. Collectively, these data illustrate that PCK2 is pivotal for bone development and metabolic homeostasis, and suggest that regulation of metformin-mediated signaling could provide a novel and practical strategy for treating metabolic skeletal dysfunction.

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Zheng Li, Muxin Yue, Boon Chin Heng, Yunsong Liu, Ping Zhang, Yongsheng Zhou. Metformin can mitigate skeletal dysplasia caused by Pck2 deficiency. International Journal of Oral Science, 2022, 14(1): 54 DOI:10.1038/s41368-022-00204-1

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References

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[1]	Shah HN, . Craniofacial and long bone development in the context of distraction osteogenesis. Plast. Reconstr. Surg., 2021, 147: 54e-65e.

[2]	Yadav, P. S. et al. Stat3 loss in mesenchymal progenitors causes Job syndrome-like skeletal defects by reducing Wnt/β-catenin signaling. Proc. Natl. Acad. Sci. USA 118, e2020100118 (2021).

[3]	Zhou S, . STAT3 is critical for skeletal development and bone homeostasis by regulating osteogenesis. Nat. Commun., 2021, 12

[4]	Kwon EK, . The role of Ellis-Van Creveld 2(EVC2) in mice during cranial bone development. Anat. Rec. (Hoboken), 2018, 301: 46-55.

[5]	Suzuki, A. et al. Role of metabolism in bone development and homeostasis. Int. J. Mol. Sci. 21, 8992 (2020).

[6]	Méndez-Lucas A, . PEPCK-M expression in mouse liver potentiates, not replaces, PEPCK-C mediated gluconeogenesis. J. Hepatol., 2013, 59: 105-113.

[7]	Beale EG, Harvey BJ, Forest C. PCK1 and PCK2 as candidate diabetes and obesity genes. Cell Biochem Biophys., 2007, 48: 89-95.

[8]	Yu S, Meng S, Xiang M, Ma H. Phosphoenolpyruvate carboxykinase in cell metabolism: Roles and mechanisms beyond gluconeogenesis. Mol. Metab., 2021, 53: 101257.

[9]	Li Z, . Mitochondrial phosphoenolpyruvate carboxykinase regulates osteogenic differentiation by modulating AMPK/ULK1-dependent autophagy. Stem Cells, 2019, 37: 1542-1555.

[10]	Li Z, . The PCK2-glycolysis axis assists three-dimensional-stiffness maintaining stem cell osteogenesis. Bioact. Mater., 2022, 18: 492-506.

[11]	Yan W, Li X. Impact of diabetes and its treatments on skeletal diseases. Front. Med., 2013, 7: 81-90.

[12]	Qin W, . Novel calcium phosphate cement with metformin-laded chitosan for odontogenic differentiation of human dental pulp cells. Stem Cells Int., 2018, 2018: 7173481.

[13]	Wang P, . Metformin induces osteoblastic differentiation of human induced pluripotent stem cell-derived mesenchymal stem cells. J. Tissue Eng. Regen. Med., 2018, 12: 437-446.

[14]	McKenzie J, . Osteocyte death and bone overgrowth in mice lacking fibroblast growth factor receptors 1 and 2 in mature osteoblasts and osteocytes. J. Bone Min. Res., 2019, 34: 1660-1675.

[15]	Carvalho MS, Cabral JM, da Silva CL, Vashishth D. Synergistic effect of extracellularly supplemented osteopontin and osteocalcin on stem cell proliferation, osteogenic differentiation, and angiogenic properties. J. Cell Biochem., 2019, 120: 6555-6569.

[16]	Grasmann G, Smolle E, Olschewski H, Leithner K. Gluconeogenesis in cancer cells - Repurposing of a starvation-induced metabolic pathway?. Biochim Biophys. Acta Rev. Cancer, 2019, 1872: 24-36.

[17]	Greenhill C. Metabolism: Role of bone in glucose metabolism. Nat. Rev. Endocrinol., 2018, 14: 191.

[18]	Lieben L, Callewaert F. & Bouillon, R. Bone and metabolism: a complex crosstalk. Horm. Res., 2009, 71: 134-138.

[19]	Puchalska P, Crawford PA. Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics. Cell Metab., 2017, 25: 262-284.

[20]	Puchalska P, Crawford PA. Metabolic and signaling roles of ketone bodies in health and disease. Annu Rev. Nutr., 2021, 41: 49-77.

[21]	Williams NC, O’Neill LAJ. A Role for the krebs cycle intermediate citrate in metabolic reprogramming in innate immunity and inflammation. Front Immunol., 2018, 9: 141.

[22]	Vincent EE, . Mitochondrial phosphoenolpyruvate carboxykinase regulates metabolic adaptation and enables glucose-independent tumor growth. Mol. Cell, 2015, 60: 195-207.

[23]	Gannon NP, Schnuck JK, Vaughan RA. BCAA metabolism and insulin sensitivity - dysregulated by metabolic status?. Mol. Nutr. Food Res., 2018, 62: e1700756.

[24]	Zemdegs J, . Metformin promotes anxiolytic and antidepressant-like responses in insulin-resistant mice by decreasing circulating branched-chain amino acids. J. Neurosci., 2019, 39: 5935-5948.

[25]	Das V, . Early treatment with metformin in a mice model of complex regional pain syndrome reduces pain and edema. Anesth. Analg., 2020, 130: 525-534.

[26]	Franks EM, . Intracranial and hierarchical perspective on dietary plasticity in mammals. Zool. (Jena.), 2017, 124: 30-41.

[27]	Thompson KD, Weiss-Bilka HE, McGough EB, Ravosa MJ. Bone up: craniomandibular development and hard-tissue biomineralization in neonate mice. Zool. (Jena.), 2017, 124: 51-60.

[28]	Blumer MJF. Bone tissue and histological and molecular events during development of the long bones. Ann. Anat., 2021, 235: 151704.

[29]	McCarthy AD, Cortizo AM, Sedlinsky C. Metformin revisited: Does this regulator of AMP-activated protein kinase secondarily affect bone metabolism and prevent diabetic osteopathy. World J. Diabetes, 2016, 7: 122-133.

[30]	Duan X, Bradbury SR, Olsen BR, Berendsen AD. VEGF stimulates intramembranous bone formation during craniofacial skeletal development. Matrix Biol., 2016, 52-54: 127-140.

[31]	Robling AG, Bonewald LF. The osteocyte: new insights. Annu Rev. Physiol., 2020, 82: 485-506.

[32]	Raggatt LJ, Partridge NC. Cellular and molecular mechanisms of bone remodeling. J. Biol. Chem., 2010, 285: 25103-25108.

[33]	Gkastaris K, . Obesity, osteoporosis and bone metabolism. J. Musculoskelet. Neuronal Interact., 2020, 20: 372-381.

[34]	Jiang Y, . Loss of Hilnc prevents diet-induced hepatic steatosis through binding of IGF2BP2. Nat. Metab., 2021, 3: 1569-1584.

[35]	Olswang Y, . A mutation in the peroxisome proliferator-activated receptor gamma-binding site in the gene for the cytosolic form of phosphoenolpyruvate carboxykinase reduces adipose tissue size and fat content in mice. Proc. Natl. Acad. Sci. USA, 2002, 99: 625-630.

[36]	Franckhauser S, . Adipose overexpression of phosphoenolpyruvate carboxykinase leads to high susceptibility to diet-induced insulin resistance and obesity. Diabetes, 2006, 55: 273-280.

[37]	Franckhauser S, . Increased fatty acid re-esterification by PEPCK overexpression in adipose tissue leads to obesity without insulin resistance. Diabetes, 2002, 51: 624-630.

[38]	Yang M, Vousden KH. Serine and one-carbon metabolism in cancer. Nat. Rev. Cancer, 2016, 16: 650-662.

[39]	Li X, . Regulation of chromatin and gene expression by metabolic enzymes and metabolites. Nat. Rev. Mol. Cell Biol., 2018, 19: 563-578.

[40]	Newgard CB, . A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab., 2009, 9: 311-326.

[41]	Mahendran Y, . Genetic evidence of a causal effect of insulin resistance on branched-chain amino acid levels. Diabetologia, 2017, 60: 873-878.

[42]	Vriens K, . Evidence for an alternative fatty acid desaturation pathway increasing cancer plasticity. Nature, 2019, 566: 403-406.

[43]	Prentice KJ, . The furan fatty acid metabolite CMPF is elevated in diabetes and induces β cell dysfunction. Cell Metab., 2014, 19: 653-666.

[44]	Wang Y, . Metformin improves mitochondrial respiratory activity through activation of AMPK. Cell Rep., 2019, 29: 1511-1523.e1515.

[45]	McCreight LJ, Bailey CJ, Pearson ER. Metformin and the gastrointestinal tract. Diabetologia, 2016, 59: 426-435.

[46]	Schommers P, . Metformin causes a futile intestinal-hepatic cycle which increases energy expenditure and slows down development of a type 2 diabetes-like state. Mol. Metab., 2017, 6: 737-747.

[47]	Geerling JJ, . Metformin lowers plasma triglycerides by promoting VLDL-triglyceride clearance by brown adipose tissue in mice. Diabetes, 2014, 63: 880-891.

[48]	Kim EK, . Metformin prevents fatty liver and improves balance of white/brown adipose in an obesity mouse model by inducing FGF21. Mediators Inflamm., 2016, 2016: 5813030.

[49]	Jiating L, Buyun J, Yinchang Z. Role of metformin on osteoblast differentiation in type 2 diabetes. Biomed. Res Int, 2019, 2019: 9203934.

[50]	Baeza-Flores GDC, . Metformin: a prospective alternative for the treatment of chronic pain. Front Pharm., 2020, 11: 558474.

[51]	Smieszek, A., Tomaszewski, K. A., Kornicka, K. & Marycz, K. Metformin promotes osteogenic differentiation of adipose-derived stromal cells and exerts pro-osteogenic Effect stimulating bone rgeneration. J. Clin. Med. 7, 482 (2018).

[52]	Qu L, . Metformin-loaded nanospheres-laden photocrosslinkable gelatin hydrogel for bone tissue engineering. J. Mech. Behav. Biomed. Mater., 2021, 116: 104293.

[53]	Jeyabalan J, Shah M, Viollet B, Chenu C. AMP-activated protein kinase pathway and bone metabolism. J. Endocrinol., 2012, 212: 227-290.

[54]	Kanazawa I. Interaction between bone and glucose metabolism. Endocr. J., 2017, 64: 1043-1053.

[55]	Linder M, . EGFR controls bone development by negatively regulating mTOR-signaling during osteoblast differentiation. Cell Death Differ., 2018, 25: 1094-1106.

[56]	Ma T, . Low-dose metformin targets the lysosomal AMPK pathway through PEN2. Nature, 2022, 603: 159-165.

[57]	Rendina-Ruedy E, Rosen CJ. Lipids in the bone marrow: an evolving perspective. Cell Metab., 2020, 31: 219-231.

[58]	Cawthorn WP, . Bone marrow adipose tissue is an endocrine organ that contributes to increased circulating adiponectin during caloric restriction. Cell Metab., 2014, 20: 368-375.

[59]	Fan Y, . Parathyroid hormone directs bone marrow mesenchymal cell fate. Cell Metab., 2017, 25: 661-672.

[60]	Scheller EL, Burr AA, MacDougald OA, Cawthorn WP. Inside out: Bone marrow adipose tissue as a source of circulating adiponectin. Adipocyte, 2016, 5: 251-269.

[61]	Zhang M, . Osteoblast-specific knockout of the insulin-like growth factor (IGF) receptor gene reveals an essential role of IGF signaling in bone matrix mineralization. J. Biol. Chem., 2002, 277: 44005-44012.

[62]	Zhao, X. et al. Expression of an active Gα(s) mutant in skeletal stem cells is sufficient and necessary for fibrous dysplasia initiation and maintenance. Proc. Natl. Acad. Sci. USA 115, E428–E437 (2018).