Bone Morphogenetic Proteins in Obesity Management: Therapeutic Potential and Challenges Beyond the Skeleton

Abstract

Bone morphogenetic proteins (BMPs) are bone-derived osteokines that regulate energy metabolism and combat obesity by promoting brown adipocyte differentiation. BMP4, BMP7, BMP8B, and BMP9 are highly expressed in osteoblasts and bone matrix, from which they are released into circulation. They act as endocrine factors that induce brown adipogenesis, increase mitochondrial biogenesis, and increase thermogenesis via conserved signaling pathways (Smad, MAPK, and PGC1α). Concurrently, these BMPs maintain skeletal homeostasis and mediate crosstalk between bone and metabolic organs, including adipose tissue and the hypothalamus, thereby regulating appetite and energy balance. Preclinical studies have confirmed that BMP-based interventions can increase energy expenditure, improve insulin sensitivity, and alleviate obesity-related complications. However, clinical translation remains hindered by adverse effects, short half-lives, and obesity-induced BMP resistance. This review first elucidates the peripheral and central regulatory mechanisms of BMPs in energy metabolism, clarifies the subtype-specific metabolic effects of major BMPs, further evaluates their therapeutic potential against obesity and metabolic syndrome, and finally analyzes the core obstacles to clinical implementation and corresponding solution strategies.

Graphical abstract

Keywords

Bone morphogenetic proteins / Obesity / Energy metabolism / Brown adipose tissue / Thermogenesis / Adipose tissue browning / Osteokines / Metabolic syndrome

References

[1] Yang M, Liu S, Zhang C. The related metabolic diseases and treatments of obesity. Healthcare., 2022, 10(9): 1616.

[2] Wu J, Cohen P, Spiegelman BM. Adaptive thermogenesis in adipocytes: Is beige the new brown?. Genes Dev., 2013, 27(3): 234-250.

[3] Virtanen KA, Lidell ME, Orava J, et al.. Functional brown adipose tissue in healthy adults. N Engl J Med., 2009, 360(15): 1518-1525.

[4] Cypess AM, Lehman S, Williams G, et al.. Identification and importance of brown adipose tissue in adult humans. N Engl J Med., 2009, 360(15): 1509-1517.

[5] Chondronikola M, Volpi E, Børsheim E, et al.. Brown adipose tissue improves whole-body glucose homeostasis and insulin sensitivity in humans. Diabetes., 2014, 63(12): 4089-4099.

[6] Jensen GS, Leon-Palmer NE, Townsend KL. Bone morphogenetic proteins (BMPs) in the central regulation of energy balance and adult neural plasticity. Metabolism., 2021, 123. ArticleID: 154837

[7] Zhou R, Guo Q, Xiao Y, et al.. Endocrine role of bone in the regulation of energy metabolism. Bone Res., 2021, 9: 25.

[8] Hogan BL. Bone morphogenetic proteins: multifunctional regulators of vertebrate development. Genes Dev., 1996, 10(13): 1580-1594.

[9] Chen Y, Ma B, Wang X, et al.. Potential functions of the BMP family in bone, obesity, and glucose metabolism. J Diabetes Res., 2021, 2021: 6707464.

[10] Whittle AJ, Carobbio S, Martins L, et al.. BMP8B increases brown adipose tissue thermogenesis through both central and peripheral actions. Cell., 2012, 149(4): 871-885.

[11] Shaw A, Tóth BB, Arianti R, et al.. BMP7 increases UCP1-dependent and independent thermogenesis with a unique gene expression program in human neck area derived adipocytes. Pharmaceuticals., 2021, 14(11): 1078.

[12] Smith C, Lin X, Parker L, et al.. The role of bone in energy metabolism: a focus on osteocalcin. Bone., 2024, 188. ArticleID: 117238

[13] Pacicca DM, Brown T, Watkins D, et al.. Elevated glucose acts directly on osteocytes to increase sclerostin expression in diabetes. Sci Rep., 2019, 9: 17353.

[14] Minniti G, Pescinini-Salzedas LM, dos Santos Almeida, Minniti G, et al.. Organokines, sarcopenia, and metabolic repercussions: the vicious cycle and the interplay with exercise. Int J Mol Sci., 2022, 23(21): 13452.

[15] Lee NK, Sowa H, Hinoi E, et al.. Endocrine regulation of energy metabolism by the skeleton. Cell., 2007, 130(3): 456-469.

[16] Kusu N, Laurikkala J, Imanishi M, et al.. Sclerostin is a novel secreted osteoclast-derived bone morphogenetic protein antagonist with unique ligand specificity. J Biol Chem., 2003, 278(26): 24113-24117.

[17] Wang W, Seale P. Control of brown and beige fat development. Nat Rev Mol Cell Biol., 2016, 17(11): 691-702.

[18] Huang H, Song TJ, Li X, et al.. BMP signaling pathway is required for commitment of C3H10T1/2 pluripotent stem cells to the adipocyte lineage. Proc Natl Acad Sci U S A., 2009, 106(31): 12670-12675.

[19] Tseng YH, Kokkotou E, Schulz TJ, et al.. New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature., 2008, 454(7207): 1000-1004.

[20] Okla M, Ha JH, Temel RE, et al.. BMP7 drives human adipogenic stem cells into metabolically active beige adipocytes. Lipids., 2015, 50(2): 111-120.

[21] Zhang L, Cai X, Ma F, et al.. Two-step regulation by matrix Gla protein in brown adipose cell differentiation. Mol Metab., 2024, 80. ArticleID: 101870

[22] Townsend KL, Pritchard E, Coburn JM, et al.. Silk hydrogel-mediated delivery of bone morphogenetic protein 7 directly to subcutaneous white adipose tissue increases browning and energy expenditure. Front Bioeng Biotechnol., 2022, 10. ArticleID: 884601

[23] Tseng YH, Cypess AM, Kahn CR. Cellular bioenergetics as a target for obesity therapy. Nat Rev Drug Discov., 2010, 9(6): 465-482.

[24] Kim SH, Plutzky J. Brown fat and browning for the treatment of obesity and related metabolic disorders. Diabetes Metab J., 2016, 40(1): 12.

[25] Um JH, Park SY, Hur JH, et al.. Bone morphogenic protein 9 is a novel thermogenic hepatokine secreted in response to cold exposure. Metabolism., 2022, 129. ArticleID: 155139

[26] Wang Y, Ma C, Sun T, et al.. Potential roles of bone morphogenetic protein-9 in glucose and lipid homeostasis. J Physiol Biochem., 2020, 76(4): 503-512.

[27] Song D, Zhang F, Reid RR, et al.. BMP9 induces osteogenesis and adipogenesis in the immortalized human cranial suture progenitors from the patent sutures of craniosynostosis patients. J Cellular Molecular Medi., 2017, 21(11): 2782-2795.

[28] Kuo MM, Kim S, Tseng CY, et al.. BMP-9 as a potent brown adipogenic inducer with anti-obesity capacity. Biomaterials., 2014, 35(10): 3172-3179.

[29] Modica S, Wolfrum C. The dual role of BMP4 in adipogenesis and metabolism. Adipocyte., 2017, 6(2): 141-146.

[30] Shu B, Zhang M, Xie R, et al.. BMP2, but not BMP4, is crucial for chondrocyte proliferation and maturation during endochondral bone development. J Cell Sci., 2011, 124(20): 3428-3440.

[31] Qian SW, Liu Y, Wang J, et al.. BMP4 cross-talks with estrogen/ERα signaling to regulate adiposity and glucose metabolism in females. EBioMedicine., 2016, 11: 91-100.

[32] Mu WJ, Song YJ, Yang LJ, et al.. Bone morphogenetic protein 4 in perivascular adipose tissue ameliorates hypertension through regulation of angiotensinogen. Front Cardiovasc Med., 2022, 9: 1038176.

[33] Hoffmann JM, Grünberg JR, Church C, et al.. BMP4 gene therapy in mature mice reduces BAT activation but protects from obesity by browning subcutaneous adipose tissue. Cell Rep., 2017, 20(5): 1038-1049.

[34] Xue R, Wan Y, Zhang S, et al.. Role of bone morphogenetic protein 4 in the differentiation of brown fat-like adipocytes. Am J Physiol Endocrinol Metab., 2014, 306(4): E363-E372.

[35] Modica S, Straub LG, Balaz M, et al.. Bmp4 promotes a brown to white-like adipocyte shift. Cell Rep., 2016, 16(8): 2243-2258.

[36] Mu W, Qian S, Song Y, et al.. BMP4-mediated browning of perivascular adipose tissue governs an anti-inflammatory program and prevents atherosclerosis. Redox Biol., 2021, 43. ArticleID: 101979

[37] Liu X, Jiang X, Hu J, et al.. Exercise attenuates high-fat diet-induced PVAT dysfunction through improved inflammatory response and BMP4-regulated adipose tissue browning. Front Nutr., 2024, 11: 1393343.

[38] Qian SW, Tang Y, Li X, et al.. BMP4-mediated brown fat-like changes in white adipose tissue alter glucose and energy homeostasis. Proc Natl Acad Sci U S A., 2013, 110(9): E798-807.

[39] Ziqubu K, Dludla PV, Moetlediwa MT, et al.. Disease progression promotes changes in adipose tissue signatures in type 2 diabetic (db/db) mice: The potential pathophysiological role of batokines. Life Sci., 2023, 313. ArticleID: 121273

[40] Zhong S, Du X, Gao J, et al.. BMP8B activates both SMAD2/3 and NF-κB signals to inhibit the differentiation of 3T3-L1 preadipocytes into mature adipocytes. Nutrients., 2024, 16(1): 64.

[41] Kiefer FW. The significance of beige and brown fat in humans. Endocr Connect., 2017, 6(5): R70-R79.

[42] Zhang L, Luo Q, Shu Y, et al.. Transcriptomic landscape regulated by the 14 types of bone morphogenetic proteins (BMPs) in lineage commitment and differentiation of mesenchymal stem cells (MSCs). Genes Dis., 2019, 6(3): 258-275.

[43] Urisarri A, González-García I, Estévez-Salguero Á, et al.. BMP8 and activated brown adipose tissue in human newborns. Nat Commun., 2021, 12: 5274.

[44] Zhong S, Li H, Wang YS, et al.. Bmp8a is an essential positive regulator of antiviral immunity in zebrafish. Commun Biol., 2021, 4: 318.

[45] Zhong S, Chen L, Li X, et al.. Bmp8a deletion leads to obesity through regulation of lipid metabolism and adipocyte differentiation. Commun Biol., 2023, 6: 824.

[46] Martins L, Seoane-Collazo P, Contreras C, et al.. A functional link between AMPK and orexin mediates the effect of BMP8B on energy balance. Cell Rep., 2016, 16(8): 2231-2242.

[47] Elsen M, Raschke S, Tennagels N, et al.. BMP4 and BMP7 induce the white-to-brown transition of primary human adipose stem cells. Am J Physiol Cell Physiol., 2014, 306(5): C431-C440.

[48] Kumar A, Kumar V, Rattan V, et al.. Secretome proteins regulate comparative osteogenic and adipogenic potential in bone marrow and dental stem cells. Biochimie., 2018, 155: 129-139.

[49] Casana E, Jimenez V, Jambrina C, et al.. AAV-mediated BMP7 gene therapy counteracts insulin resistance and obesity. Mol Ther Meth Clin Dev., 2022, 25: 190-204.

[50] Boon MR, van den Berg SAA, Wang Y, et al.. BMP7 activates brown adipose tissue and reduces diet-induced obesity only at subthermoneutrality. PLoS One., 2013, 8(9. ArticleID: e74083

[51] Betz MJ, Enerbäck S. Human brown adipose tissue: what we have learned so far. Diabetes., 2015, 64(7): 2352-2360.

[52] Schulz TJ, Huang TL, Tran TT, et al.. Identification of inducible brown adipocyte progenitors residing in skeletal muscle and white fat. Proc Natl Acad Sci U S A., 2011, 108(1): 143-148.

[53] Gustafson B, Hammarstedt A, Hedjazifar S, et al.. BMP4 and BMP antagonists regulate human white and beige adipogenesis. Diabetes., 2015, 64(5): 1670-1681.

[54] Blázquez-Medela AM, Jumabay M, Boström KI. Beyond the bone: Bone morphogenetic protein signaling in adipose tissue. Obes Rev., 2019, 20(5): 648-658.

[55] Acosta JR, Douagi I, Andersson DP, et al.. Increased fat cell size: a major phenotype of subcutaneous white adipose tissue in non-obese individuals with type 2 diabetes. Diabetologia., 2016, 59(3): 560-570.

[56] Wang X, Ma B, Chen J, et al.. Glucagon-like peptide-1 improves fatty liver and enhances thermogenesis in brown adipose tissue via inhibiting BMP4-related signaling pathway in high-fat-diet-induced obese mice. Int J Endocrinol., 2021, 2021: 6620289.

[57] Qian SW, Wu MY, Wang YN, et al.. BMP4 facilitates beige fat biogenesis via regulating adipose tissue macrophages. J Mol Cell Biol., 2019, 11(1): 14-25.

[58] Townsend KL, Suzuki R, Huang TL, et al.. Bone morphogenetic protein 7 (BMP7) reverses obesity and regulates appetite through a central mTOR pathway. FASEB J., 2012, 26(5): 2187-2196.

[59] Würfel M, Blüher M, Stumvoll M, et al.. Adipokines as clinically relevant therapeutic targets in obesity. Biomedicines., 2023, 11(5): 1427.

[60] Townsend KL, Madden CJ, Blaszkiewicz M, et al.. Reestablishment of energy balance in a male mouse model with POMC neuron deletion of BMPR1A. Endocrinology., 2017, 158(12): 4233-4245.

[61] Mestres-Arenas A, Villarroya J, Giralt M, et al.. A differential pattern of batokine expression in perivascular adipose tissue depots from mice. Front Physiol., 2021, 12. ArticleID: 714530

[62] Rial-Pensado E, Freire-Agulleiro O, Ríos M, et al.. Obesity induces resistance to central action of BMP8B through a mechanism involving the BBSome. Mol Metab., 2022, 59. ArticleID: 101465

[63] Zhang Z, Yang D, Xiang J, et al.. Non-shivering thermogenesis signalling regulation and potential therapeutic applications of brown adipose tissue. Int J Biol Sci., 2021, 17(11): 2853-2870.

[64] Guo Y, Wan Z, Zhao P, et al.. Ultrasound triggered topical delivery of Bmp7 mRNA for white fat browning induction via engineered smart exosomes. J Nanobiotechnol., 2021, 19(1): 402.

[65] Kuo MC, Nguyen PH, Jeon YH, et al.. MB109 as bioactive human bone morphogenetic protein-9 refolded and purified from E. coli inclusion bodies. Microb Cell Fact., 2014, 13(1): 29.

[66] Lecanda F, Avioli LV, Cheng SL. Regulation of bone matrix protein expression and induction of differentiation of human osteoblasts and human bone marrow stromal cells by bone morphogenetic protein-2. J Cell Biochem., 1997, 67(3): 386-398.

[67] James AW, LaChaud G, Shen J, et al.. A review of the clinical side effects of bone morphogenetic protein-2. Tissue Eng Part B Rev., 2016, 22(4): 284-297.

[68] Zara JN, Siu RK, Zhang X, et al.. High doses of bone morphogenetic protein 2 induce structurally abnormal bone and InflammationIn vivo. Tissue Eng Part A., 2011, 17(9–10): 1389-1399.

[69] Fan J, Zhang X, Kang M, et al.. Complementary modulation of BMP signaling improves bone healing efficiency. Biomaterials., 2023, 302. ArticleID: 122335

[70] Chen K, Cheong LY, Gao Y, et al.. Adipose-targeted triiodothyronine therapy counteracts obesity-related metabolic complications and atherosclerosis with negligible side effects. Nat Commun., 2022, 13: 7838.

[71] Blaszkiewicz M, Tao T, Mensah-Arhin K, et al.. Gene therapy approaches for obesity-induced adipose neuropathy: Device-targeted AAV-mediated neurotrophic factor delivery to adipocytes in subcutaneous adipose. Mol Ther., 2024, 32(5): 1407-1424.

[72] Kudaibergen G, Mukhlis S, Mukhambetova A, et al.. Repair of rat calvarial critical-sized defects using heparin-conjugated fibrin hydrogel containing BMP-2 and adipose-derived pericytes. Bioengineering., 2024, 11(5): 437.

[73] Infarinato NR, Stewart KS, Yang Y, et al.. BMP signaling: at the gate between activated melanocyte stem cells and differentiation. Genes Dev., 2020, 34(23–24): 1713-1734.

[74] Kim MJ, Choe S. BMPs and their clinical potentials. BMB Rep., 2011, 44(10): 619-634.

[75] Schulz TJ, Graja A, Huang TL, et al.. Loss of BMP receptor type 1A in murine adipose tissue attenuates age-related onset of insulin resistance. Diabetologia., 2016, 59(8): 1769-1777.

Funding

Chongqing Sports Research Project(B202421)

RIGHTS & PERMISSIONS

The Author(s), under exclusive licence to the Huazhong University of Science and Technology