Key Takeaways & Executive Findings
- •• Hedgehog signaling pathway activation promotes osteoblast differentiation and bone formation via Runx2 and Wnt crosstalk, offering a dual therapeutic approach for diabetic osteoporosis. • The pathway enhances glucose metabolism and insulin sensitivity through PI3K-Akt and AMPK signaling, addressing the diabetic component of the disease. • Hedgehog signaling reduces advanced glycation end products, mitigating oxidative stress and β-cell apoptosis, thus preserving glycemic control. • Targeting Hedgehog with activators, such as tetrahedral framework nucleic acid/quercetin complexes, shows preclinical promise as a specific drug therapy for diabetic osteoporosis.
Abstract
BACKGROUND: The Hedgehog signaling pathway has been demonstrated to play a crucial role in osteogenesis, promoting osteoblast differentiation and maturation, maintaining bone metabolic homeostasis, enhancing glucose metabolism, and improving insulin resistance, thereby offering therapeutic potential for both osteoporosis and diabetes. Currently, the primary treatment strategy for diabetic osteoporosis involves a combination of hypoglycemic agents and calcium supplements. However, studies indicate that some antidiabetic drugs may disrupt calcium and phosphate balance, accelerating bone loss. Therefore, identifying effective therapeutic targets for diabetic osteoporosis is imperative. OBJECTIVE: To explore the relationship between Hedgehog signaling pathway activation and diabetic osteoporosis pathogenesis, providing a reference and theoretical basis for the subsequent development of targeted drugs for diabetic osteoporosis. METHODS: Literature on the link between Hedgehog signaling pathway transduction and the pathological mechanism of diabetic osteoporosis published from the inception of PubMed and CNKI databases up to July 2025 was retrieved. Chinese search terms included "diabetic osteoporosis, Hedgehog signaling pathway, osteogenic differentiation, glucose metabolism, Runx2, advanced glycation end products"; English search terms included "diabetic osteoporosis, hedgehog signaling pathway, osteogenic differentiation, glucose metabolism, Runx2, AGEs". A total of 81 articles were included after screening for relevance and avoiding duplication. RESULTS AND CONCLUSION: (1) The prevention and treatment of diabetic osteoporosis requires simultaneous regulation of bone metabolism and glucose metabolism. Activation of the Hedgehog signaling pathway promotes osteoblast differentiation and increases bone mass by initiating transcription of the target gene Runt-related transcription factor 2 and synergistically regulating with the Wnt signaling pathway. (2) Additionally, Hedgehog signaling pathway expression promotes the activation of phosphatidylinositol 3-kinase-protein kinase B and AMP-activated protein kinase signaling pathways, and reduces advanced glycation end products. Activation of these pathways enhances glucose transport and utilization, improving glucose metabolism, while reduced AGEs alleviate stress responses, inhibit pancreatic β-cell apoptosis, and maintain glucose homeostasis.
1. Introduction
Current prevention and treatment strategies for diabetic osteoporosis primarily combine antidiabetic drugs with osteoporosis medications. However, certain hypoglycemic agents, such as thiazolidinediones and sodium-glucose cotransporter 2 inhibitors, carry risks of accelerating bone loss and disrupting calcium and phosphate balance, which antagonize the treatment of diabetic osteoporosis. Therefore, developing targeted drugs that can precisely and effectively prevent and treat diabetic osteoporosis has become a top priority in clinical research.
The Hedgehog signaling pathway has been extensively studied in cancer and other types of osteoporosis. Beyond regulating cancer cell growth and osteoblast differentiation, this pathway is also implicated in the pathogenesis of diabetes. When the Hedgehog pathway is normally expressed, it enhances glucose metabolism to maintain glycemic homeostasis and rescues β-cell damage induced by insulin resistance. Notably, Hedgehog signaling expression varies among different types of osteoporosis. In diabetic osteoporosis, the pathway is suppressed due to factors such as advanced glycation end products accumulation, oxidative stress, and glucotoxicity, whereas in postmenopausal osteoporosis, excessive activation of the pathway compensates for osteoblast differentiation due to increased osteoclast activity. Given this, Hedgehog signaling pathway activators represent a promising target for clinical research in diabetic osteoporosis. However, the molecular mechanisms underlying the role of Hedgehog signaling in preventing and treating diabetic osteoporosis remain incompletely understood and lack systematic elucidation. This review therefore discusses the mechanisms by which Hedgehog signaling may combat diabetic osteoporosis, providing a theoretical foundation for future clinical studies.
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Tian Tan, Bao Shanjun (2026). Hedgehog signaling pathway and diabetic osteoporosis: a potential target for specific drug therapy. Chinese Journal of Tissue Engineering Research. https://doi.org/10.12307/2026.21324
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Frequently Asked Questions
What is the role of the Hedgehog signaling pathway in diabetic osteoporosis?
The Hedgehog signaling pathway is crucial for osteoblast differentiation and bone formation. In diabetic osteoporosis, this pathway is suppressed, and its activation can promote bone formation and improve glucose metabolism, making it a potential therapeutic target.
How does Hedgehog signaling affect glucose metabolism?
Hedgehog signaling enhances glucose metabolism by activating PI3K-Akt and AMPK pathways, which promote glucose transport and utilization, and by reducing advanced glycation end products, thereby improving insulin sensitivity and maintaining glycemic homeostasis.
What are the current treatment limitations for diabetic osteoporosis?
Current treatments combine antidiabetic drugs with calcium supplements, but some antidiabetic drugs can disrupt calcium and phosphate balance and accelerate bone loss, necessitating the development of targeted therapies.
What is the potential of Hedgehog-targeted drugs for diabetic osteoporosis?
Hedgehog-targeted drugs, such as tetrahedral framework nucleic acid/quercetin complexes, have shown promising therapeutic effects in preclinical studies, potentially offering a specific treatment for diabetic osteoporosis.
How does Hedgehog signaling interact with other pathways in bone formation?
Hedgehog signaling promotes osteoblast differentiation by initiating Runx2 transcription and synergistically interacting with the Wnt signaling pathway, thereby increasing bone mass.
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