Max Sadlowski

Background: Osteoporosis is a metabolic bone disease typically affecting individuals over 50 years of age, with a higher incidence among women.^1,2,3,4,5 The disease is marked by a significant decrease in bone density due to a variety of factors, one of the more prominent being age-related decreases in hormonal signaling and tissue turnover and repair.^1,2,3 It is believed that two main processes contribute to the development of osteoporosis: first, failure to achieve peak bone mass, which is achieved in the first three decades of life, based on a variety of factors including diet, exercise, and stress; and second is excessive bone resorption brought about by hyperactive osteoclasts or reduced cell-signaling, often associated with age-related health declines.^1,2,5 Current treatment is limited to supplement use (VitD3, calcium) and various pharmacological therapeutics (bisphosphonate, teriparatide, HRT) that are not suitable for long-term use.^1,2,3,5 Furthermore, these treatments do not improve the disease, rather they treat the symptoms and slow progression. This brings the question of stem cell utility to the forefront, as stem cells present an interesting opportunity to combat the primary cause of osteoporosis, inducing new bone growth, and potentially reversing some of the degeneration seen with long-term disease.^1,2,3,4,5 Mesenchymal stem cells harvested from bone marrow or adipose have a high recovery yield, can be grown in culture, and offer a potential solution to treating degenerative bone diseases like osteoporosis.^1,2,3,4,5

Objective: In this narrative review, we explored the mechanisms of bone turnover and deposition related to osteoporosis, showing the importance of Hedgehog (Hh) signaling in normal homeostasis and stem cell differentiation.

Search Methods: An online search in the PubMed database was conducted from 2017-2022 using the following keywords: “Hedgehog”, “Stem Cells”, “Osteoporosis”, “Treatment”.

Results: Studies indicated that Hh signaling plays a crucial role in bone homeostasis, tissue differentiation, and the normal development of mammals.^2,5 There are three different Hh ligands (Desert hedgehog Dhh, Indian Hedgehog Ihh, Sonic Hedgehog Shh), all acting via a similar mechanism.^4,5 They bind to their corresponding Patched1 receptor and inhibit its activity as a suppressor of Smo (smoothened protein), a protein which assists with Hh signal transduction.⁴ Gli1-LacZ, a synthetic transgene where the Gli-1 responsive promoter is attached to LacZ an enzyme that metabolizes X-gal sugar to a blue product which will express the betagalactosidase (lacZ) in a Gli-1 (Hh) – dependent manner, showing that blue fluorescing cells in the growth plates of mice responded to Hh signaling.⁵ Similarly, Gli1-CreERT2 reporter mice, where GFP fluoresces in cells that where Hh is active even after signaling has stopped, showed there is significant GFP seen in both tibial and femoral growth plates, proving that Hh drives osteogenic cell proliferation in long bones.^4,5

Conclusion: Studies have shown that upregulation of Hh signaling is correlated with increased bone formation.^1,2,3,4,5 Additionally, age-related declines in Hh signal transduction were noted.^2,3,4,5 More research should target the development of a Hh stimulator drug that could be used to induce the pathway selectively in osteoprogenitor cells, thereby upregulating the commitment step from precursor to committed osteogenic cell lines, driving the deposition of new bone.

Works Cited:

1. Li H, Zhou W, Sun S, Zhang T, Zhang T, Huang H, Wang M. Microfibrillar-associated protein 5 regulates osteogenic differentiation by modulating the Wnt/β-catenin and AMPK signaling pathways. Mol Med. 2021 Dec 5;27(1):153. doi: 10.1186/s10020-021-00413-0. PMID: 34865619; PMCID: PMC8647299.
2. Haraguchi R, Kitazawa R, Imai Y, Kitazawa S. Growth plate-derived hedgehog-signal-responsive cells provide skeletal tissue components in growing bone. Histochem Cell Biol. 2018 Apr;149(4):365-373. doi: 10.1007/s00418-018-1641-5. Epub 2018 Jan 22. PMID: 29356962.
3. Xiu C, Gong T, Luo N, Ma L, Zhang L, Chen J. Suppressor of fused-restrained Hedgehog signaling in chondrocytes is critical for epiphyseal growth plate maintenance and limb elongation in juvenile mice. Front Cell Dev Biol. 2022 Sep 2;10:997838. doi: 10.3389/fcell.2022.997838. PMID: 36120578; PMCID: PMC9479194.
4. Xu R, Khan SK, Zhou T, Gao B, Zhou Y, Zhou X, Yang Y. Gα_ssignaling controls intramembranous ossification during cranial bone development by regulating both Hedgehog and Wnt/β-catenin signaling. Bone Res. 2018 Nov 20;6:33. doi: 10.1038/s41413-018-0034-7. PMID: 30479847; PMCID: PMC6242855.
5. Zhang L, Fu X, Ni L, Liu C, Zheng Y, You H, Li M, Xiu C, Zhang L, Gong T, Luo N, Zhang Z, He G, Hu S, Yang H, Chen D, Chen J. Hedgehog Signaling Controls Bone Homeostasis by Regulating Osteogenic/Adipogenic Fate of Skeletal Stem/Progenitor Cells in Mice. J Bone Miner Res. 2022 Mar;37(3):559-576.