Osteogenesis Imperfecta: the Incurable Disorder

Many people may be familiar with the term “osteoporosis” – a systemic skeletal disorder that causes the deterioration of bone tissue and low bone mass, leading to bone fragility and a high fracture risk¹. Upon hearing this name, memories of the elderly and old relatives may easily come to mind for many. Indeed, osteoporosis is more prevalent amongst the elderly, and becomes more common with age².

However, in this blog post, we will shift away from the general disease and instead focus on a specific branch of osteoporosis: osteogenesis imperfecta (OI), better known as brittle bone disease.

Osteogenesis imperfecta is a group of rare inherited disorders of connective tissue, most commonly associated with excessive bone fragility caused by collagen mutations in genes³, first described by Swedish physician Olof Jakob Ekman⁶. There are a wide range of symptoms, ranging from hearing loss, recurrent chronic pain in the abdomen and constipation to pulmonary and cardiovascular complications.

As scary as it sounds, OI is a rare genetic disease, and only affects one in 15,000 ~ 20,000 people⁴. Due to the variability and the number of genes involved (there are 19 distinct genes that can contribute to OI) in the disease, as of 2021, there are 21 types of the disease, classified by the genetic mutations an OI patient has.

The most common types of OI are types I, II, III and IV, summarised in the table below⁷:

Type	Description	Gene	Mode of inheritance	Incidence
I	mild; collagen is of insufficient quantity	Null COL1A1 gene	Autosomal dominant, 34% de novo⁵	1/30,000
II	lethal in the perinatal period; collagen is fatally defective at C-terminus	COL1A2, COL1A2	Autosomal dominant, ~100% de novo⁵	1/40,000 ~ 1/100,000
III	Severe, progressive and deforming; collagen quantity is insufficient but are of low quality	COL1A1, COL1A2	Autosomal dominant, 85% de novo⁵	1/60,000
IV	variable and deforming, but usually with normal sclerae; collagen quantity is sufficient but are of low quality	COL1A1, COL1A2	Autosomal dominant, 50% de novo⁵	1/30,000

One important thing to note about this disorder is that it currently has no known treatment, medicine or surgery⁸, as the condition is caused by mutating genes, and the field of gene editing has not yet advanced to the point where it can cure genetic diseases yet.

All is not lost, however, as there are many commercially available forms of medication that can prevent deformities and bone fractures, with the two most commonly used classes of drugs being bisphosphonates and monoclonal antibodies.

Bisphosphonates are a class of drugs typically used to treat osteoporosis via slowing down bone resorption⁹ and prevents osteoclasts from adhering onto the bone surface. However, there are a few documented cases that bisphosphonates may cause the osteonecrosis of the jaw, and along with bone, joint and/or muscle pain, the drug also affects kidney function¹⁰.

Before we go into the antibody treatment, we must first understand the mechanism of action of the antibody.

In humans, two types of specialsed cells regulate bone formation and resorption: osteoblasts and osteoclasts. The behaviour of normal osteoblasts (diagram on the left) begins when a Wnt protein binds to the N-terminal extracellular domain of a Frizzled (Fz) family receptor¹¹. To facilitate the signalling process, other co-receptors may be required alongside the Fz receptor, such as the lipoprotein (LRP)-5/6¹². Upon the activation of LRP5/6, a signal is sent to other phosphoproteins within the cell cytoplasm from the Fz receptor.

Normally this is where the Wnt signalling pathway splits off into three different branches, but the one that concerns us the most is the canonical pathway. It involves the accumulation of β-catenin, a dual-function protein involved in the regulation and coordination of gene transcription, in the cytoplasm.

Under most circumstances, β-catenin is degraded by a destruction complex composed of Axin, PP2A, GSK-3 and casein kinase 1α. However, once Wnt binds Fz and LRP5/6, the destruction complex is disrupted as Axin binds to LRP5/6 and becomes dephosphorylated. Other phosphoproteins in the cytoplasm will also inhibit GSK3 activity when this happens. This will allow β-catenin to accumulate and localise to the nucleus, inducing a cellular response¹³ alongside TCF/LEF (T-cell factor/lymphoid enhancing factor) transcription factors. In osteoblasts, this would ultimately end in an increase in bone formation.

Problems arise when sclerostin, a glycoprotein encoded by the SOST gene in humans, attaches to LRP5/6 receptors and disrupts this process¹⁴. Sclerostin is expressed in osteocytes and inhibits bone formation by osteoblasts. This is because once LRP5/6 is inactivated by sclerostin, the pathway cannot proceed, and will lead to the decline in β-catenin concentrations in the osteoblast, thereby reducing bone formation.

Although osteoblast activity is itself regulated by a negative feedback system by sclerostin as well as a whole host of other hormones and inhibitory factors, in OI patients, decreased osteoblast activity by the action of sclerostin is often the cause of improper or little to no COL1A1/2 gene expression in osteoblasts, causing OI.

It must be emphasized that sclersotin is not an “evil” protein; it merely serves as a regulator for osteoblast activity. If the SOST gene responsible for the encoding of sclerostin mutates, van Buchem disease and sclerosteosis disorders may result¹⁵.

The antibody mentioned earlier is called romosozumab¹⁶ (sold under the brand Evenity). In its clinical trials, the antibody binds to sclerostin and inactivates the protein, causing an increase in osteoblast activity via the canonical Wnt signaling pathway described above.

However, the antibody also imposed severe cardiac ischemic events during phase III clinical trials.

Due to the extremely high associated risks of heart attacks, strokes and death from cardiovascular diseases¹⁶, the drug was rejected several times by the U.S. Food and Drug Administration as well as the European Medicines Agency. Although the drug was finally approved by both institutions^{16, 17}, its tortuous experiences in applying for market authorization for postmenopausal osteoporosis remain proof of just how difficult it is to approve high-risk medication.

Note that cardiovascular diseases are already a staple in many OI patients, as a Danish study in 2016 has shown¹⁸.

After understanding the effects of current available treatments, it becomes easy to see why creating a second-generation sclerostin inhibitor is particularly desirable, both to treat osteogenesis imperfecta without increasing the risk of developing cardiovascular diseases in the process. There is also a growing cardiovascular concern for OI patients during sclerostin antibody treatment, especially for those with cardiovascular abnormalities or with cardiovascular diseases history.

iGEM Team HKBU 2021 has already developed an aptamer as an alternative sclerostin inhibitor that will selectively inhibit sclerostin in a way that will inactivate its ability to bind with LRP5/6 receptors, while simultaneously preserving sclerostin’s function as a cardiovascular regulator in the human body, and has received U.S. FDA Orphan Drug Designation.